Cancer treatment is challenged by the tumor microenvironment (TME), which promotes drug resistance and cancer cell growth. This review offers a comprehensive and innovative perspective on how nanomedicine can modify the TME to enhance therapy. Strategies include using nanoparticles to improve oxygenation, adjust acidity, and alter the extracellular matrix, making treatments more effective. Additionally, nanoparticles can enhance immune responses by activating immune cells and reducing suppression within tumors. By integrating these approaches with existing therapies, such as chemotherapy and radiotherapy, nanoparticles show promise in overcoming traditional treatment barriers. The review discusses how changes in the TME can enhance the effectiveness of nanomedicine itself, creating a reciprocal relationship that boosts overall efficacy. We also highlight novel strategies aimed at exploiting and overcoming the TME, leveraging nanoparticle-based approaches for targeted cancer therapy through precise TME modulation.

Silk has emerged as an interesting candidate among protein-based nanocarriers due to its favorable properties, including biocompatibility and a broad spectrum of processing options to tune particle critical quality attributes. The silk protein conformation during storage in the middle silk gland of the silkworm is modulated by various factors, including the most abundant metallic ion, calcium ion (Ca2+). Here, we report spiking of liquid silk with calcium ions to modulate the silk nanoparticle size. Conformational and structural analyses of silk demonstrated Ca2+-induced silk assemblies that resulted in a liquid crystalline-like state, with the subsequent generation of β-sheet-enriched silk nanoparticles. Thioflavin T studies demonstrated that Ca2+ effectively induces self-assembly and conformation changes that also increased model drug loading. Ca2+ incorporation in the biopolymer feed significantly increased the nanoparticle production yield from 16 to 89%, while simultaneously enabling Ca2+ concentration-dependent particle-size tuning with a narrow polydispersity index and altered zeta potential. The resulting silk nanoparticles displayed high biocompatibility in macrophages with baseline levels of cytotoxicity and cellular inflammation. Our strategy for manufacturing biomimetic silk nanoparticles enabled overall tuning of particle size and improved yields─features that are critical for particle-based nanomedicines.

The cellular components of the tumor microenvironment (TME) comprise cancer cells and nonmalignant cells including stromal and immune cells. Exosomes are extracellular vesicles secreted by various types of cells that play a crucial role in intercellular communications within TME. The main goal of this study was to elucidate how exosomes of macrophage cells treated with doxorubicin (DOX) and DOX-loaded cyclodextrin-based nanosponges (DOX-CDNSs), affect melanoma cancer cell proliferation. For this aim, the exosomes of the murine macrophage cell line (RAW 264.7) were isolated and characterized after treating the cells with DOX and DOX-CDNSs. The results demonstrated that DOX-CDNSs at a treatment concentration of 1 µg/mL, were nontoxic for macrophages and remarkably toxic against cancer cells. However, DOX was nontoxic for both cell types at the same treatment concentration. DOX and DOX-CDNSs remarkably declined the viability of both cell types at higher concentrations (25 and 50 µg/mL). Intriguingly, the exosomes of DOX-CD-NSs treated macrophages promoted the viability of cancer cells at the treatment concentrations of 1, 20, and 40 µg/mL. While the exosomes of DOX-treated macrophages increased cell viability of cancer cells only at the lowest concentration. In conclusion, this study suggests that utilization of CD-NSs may augment the toxicity of DOX against cancer cells, while it could direct macrophages toward secreting exosomes that favor the growth of cancer cells.

Renal ischemia-reperfusion (I/R) injury is a common clinical factor for acute kidney injury (AKI). A current study investigated the renoprotective effects of the trinitroglycerine (TNG) combination with chitosan nanoparticles (CNPs) on renal I/R-induced AKI. Rats were randomly assigned to five groups (n = 8/group): Sham, I/R, TNG (50 mg/kg) + I/R, CNPs (60 mg/kg) + I/R, and TNG-CNPs + I/R. Bilateral renal pedicles were occluded for 60 min to induce ischemia. TNG, CNPs, or TNG-CNPs were administered intraperitoneally 30 min before renal ischemia. After 24 h of reperfusion, blood samples were collected, and both kidneys were removed. The left kidney was used for oxidative stress analysis. The right kidney was preserved in 10% formalin for histopathological examination via H&E staining. After renal ischemia-reperfusion injury, there was an observed increase in plasma creatinine (Cr) and blood urea nitrogen (BUN), accompanied by a decrease in glomerular filtration rate (GFR) in rats. Total oxidative stress (TOS) levels were also significantly higher in the I/R group, whereas total antioxidative capacity (TAC) was reduced. Histopathological examination revealed damage in the kidneys of rats in the I/R group. Pretreatment with the TNG-CNP formulation before I/R increased plasma and tissue TAC levels in rats. It also corrected the renal histopathological changes and functional disorders induced by I/R injury, as evidenced by reduced Cr and BUN, increased GFR, and attenuated oxidative stress. The results suggest that the TNG-CNP combination provides renoprotective effects against I/R-induced AKI by improving antioxidant status and minimizing renal injury.

Hepatocellular carcinoma (HCC) represents a significant clinical burden globally and is predicted to continue to increase in incidence for the foreseeable future. The treatment of HCC is complicated by the fact that, in the majority of cases, it develops on a background of advanced chronic inflammatory liver disease. Chronic inflammation can foster an immunosuppressive microenvironment that promotes tumour progression and metastasis. In this setting, macrophages make up a major immune component of the HCC tumour microenvironment, and in this review, we focus on their contribution to HCC development and progression. Tumour-associated macrophages (TAMs) are largely derived from infiltrating monocytes and their potent anti-inflammatory phenotype can be induced by factors that are found within the tumour microenvironment, such as growth factors, cytokines, hypoxia, and extracellular matrix (ECM) proteins. In general, experimental evidence suggest that TAMs can exhibit a variety of functions that aid HCC tumour progression, including the promotion of angiogenesis, resistance to drug therapy, and releasing factors that support tumour cell proliferation and metastasis. Despite their tumour-promoting profile, there is evidence that the underlying plasticity of these cells can be targeted to help reprogramme TAMs to drive tumour-specific immune responses. We discuss the potential for targeting TAMs therapeutically either by altering their phenotype within the HCC microenvironment or by cell therapy approaches by taking advantage of their infiltrative properties from the circulation into tumour tissue.

Cancer is a leading cause of morbidity and mortality worldwide, and an increase in incidence is estimated in the next future, due to population aging, which requires the development of highly tolerable and low-toxicity cancer treatment strategies. The use of nanotechnology to tailor treatments according to the genetic and immunophenotypic characteristics of a patient's tumor, and to allow its targeted release, can meet this need, improving the efficacy of treatment and minimizing side effects. Nanomedicine-based approach for the diagnosis and treatment of cancer is a rapidly evolving field. Several nanoformulations are currently in clinical trials, and some have been approved and marketed. However, their large-scale production and use are still hindered by an in-depth debate involving ethics, intellectual property, safety and health concerns, technical issues, and costs. Here, we survey the key approaches, with specific reference to organ-on chip technology, and cutting-edge tools, such as CRISPR/Cas9 genome editing, through which nanosystems can meet the needs for personalized diagnostics and therapy in cancer patients. An update is provided on the nanopharmaceuticals approved and marketed for cancer therapy and those currently undergoing clinical trials. Finally, we discuss the emerging avenues in the field and the challenges to be overcome for the transfer of nano-based precision oncology into clinical daily life.

Cell-mediated nanoparticle delivery systems (CMNDDs) utilize cells as carriers to deliver the drug-loaded nanoparticles. Unlike the traditional nanoparticle drug delivery approaches, CMNDDs take the advantages of cell characteristics, such as the homing capabilities of stem cells, inflammatory chemotaxis of neutrophils, prolonged blood circulation of red blood cells, and internalization of macrophages. Subsequently, CMNDDs can easily prolong the blood circulation, cross biological barriers, such as the blood-brain barrier and the bone marrow-blood barrier, and rapidly arrive at the diseased areas. Such advantageous properties make CMNDDs promising delivery candidates for precision targeting. In this review, we summarize the recent advances in CMNDDs fabrication and biomedical applications. Specifically, ligand-receptor interactions, non-covalent interactions, covalent interactions, and internalization are commonly applied in constructing CMNDDs in vitro. By hitchhiking cells, such as macrophages, red blood cells, monocytes, neutrophils, and platelets, nanoparticles can be internalized or attached to cells to construct CMNDDs in vivo. Then we highlight the recent application of CMNDDs in treating different diseases, such as cancer, central nervous system disorders, lung diseases, and cardiovascular diseases, with a brief discussion about challenges and future perspectives in the end.

Breast cancer is the most diagnosed malignancy and major cause of cancer death among women population in the worldwide. Ferroptosis is a recently discovered iron-dependent regulated cell death involved in tumor progression and therapeutic response. Moreover, increasing studies have implied that ferroptosis is a promising approach to eliminating cancer cells like developing iron nanoparticles as a therapeutic agent. However, resistance to ferroptosis is a vital distinctive hallmark of cancer. Therefore, further investigation of the mechanism of ferroptosis resistance to enhance its tumor sensitivity is essential for ferroptosis-target breast cancer therapy. Our results revealed that the activation of C5a/C5aR pathway can drive resistance to ferroptosis and reshaping breast cancer immune microenvironment. Accordingly, loading PEG-Fe3O4 with C5aRA significantly improved the anti-tumor effect of PEG- Fe3O4 by inhibiting ferroptosis resistance and increasing macrophage polarization toward M1 phenotype. Our findings presented a novel cancer therapy strategy that combined cancer cell metal metabolism regulation and immunotherapy. The study also provided support for further evaluation of PEG- Fe3O4@C5aRA as a novel therapeutic strategy for breast cancer in clinical trials.

Macrophages play a pivotal role in the internalization and processing of administered nanoparticles (NPs). Furthermore, the phagocytic capacity and immunological properties of macrophages can vary depending on their microenvironment, exhibiting a spectrum of polarization states ranging from pro-inflammatory M1 to anti-inflammatory M2. However, previous research investigating this phenotype-dependent interaction with NPs has predominantly relied on semi-quantitative techniques or conventional metrics to assess intracellular NPs. Here, we focus on the interaction of human monocyte-derived macrophage phenotypes (M1-like and M2-like) with gold NPs (AuNPs) by combining population-based metrics and single-cell analysis by focused ion beam-scanning electron microscopy (FIB-SEM). The multimodal analysis revealed phenotype-dependent response and uptake behavior differences, becoming more pronounced after 48 hours. The study also highlighted phenotype-dependent cell-to-cell heterogeneity in AuNPs uptake and variability in particle number at the single-cell level, which was particularly evident in M2-like macrophages, which increases with time, indicating enhanced heteroscedasticity. Future efforts to design NPs targeting macrophages should consider the phenotypic variations and the distribution of NPs concentrations within a population, including the influence of cell-to-cell heterogeneity. This comprehensive understanding will be critical in developing safe and effective NPs to target different macrophage phenotypes.

Antimony-doped tin oxide nanoparticles (ATO NPs) have emerged as a promising tool in biomedical applications, namely robust photothermal effects upon near-infrared (NIR) light exposure, enabling controlled thermal dynamics to induce spatial cell death. This study investigated the interplay between ATO NPs and macrophages, understanding cellular uptake and cytokine release. ATO NPs demonstrated biocompatibility with no impact on macrophage viability and cytokine secretion. These findings highlight the potential of ATO NPs for inducing targeted cell death in cancer treatments, leveraging their feasibility, unique NIR properties, and safe interactions with immune cells. ATO NPs offer a transformative platform with significant potential for future biomedical applications by combining photothermal capabilities and biocompatibility.

In this article we discuss how nanoparticles (NPs) of different compositions may interact with and be internalized by cells, and the consequences of that for cellular functions. A large number of NPs are made with the intention to improve cancer treatment, the goal being to increase the fraction of injected drug delivered to the tumor and thereby improve the therapeutic effect and decrease side effects. Thus, we discuss how NPs are delivered to tumors and some challenges related to investigations of biodistribution, pharmacokinetics, and excretion. Finally, we discuss requirements for bringing NPs into clinical use and aspects when it comes to usage of complex and slowly degraded or nondegradable NPs.

Anionic synthetic polypeptides are promising candidates as standalone bone-targeting drug carriers. Nevertheless, the structure-property relationship of the bone-targeting ability of polypeptides remains largely unexplored. Herein we report the optimization of the in vitro and in vivo bone-targeting ability of poly(glutamic acid)s (PGAs) by altering their chain lengths and backbone chirality. PGA 100-mers exhibited higher hydroxyapatite affinity in vitro, but their rapid macrophage clearance limited their targeting ability. Shorter PGA was therefore favored in terms of in vivo bone targeting. Meanwhile, the backbone chirality showed less significant impact on the in vitro and in vivo targeting behavior. This study highlights the modulation of structural parameters on the bone-targeting performance of anionic polypeptides, shedding light on the future design of polypeptide-based carriers.

Photodynamic therapy (PDT) uses a photosensitizer to generate reactive oxygen species (ROS) that kill target cells. In cancer treatments, PDT can potentially induce immunogenic cell death (ICD), which is characterized by a well-controlled exposure of damage-associated molecular patterns (DAMPs) that activate dendritic cells (DCs) and consequently modulate the immune response in the tumor microenvironment. However, PDT still has limitations, such as the activity of photosensitizers in aqueous media and poor bioavailability. Therefore, a new photosensitizer system, SLN-AlPc, has been developed to improve the therapeutic efficacy of PDT. In vitro experiments showed that the light-excited nanocarrier increased ROS production in murine melanoma B16-F10 cells and modulated the profile of DCs. PDT induced cell death accompanied by the exposure of DAMPs and the formation of autophagosomes. In addition, the DCs exposed to PDT-treated B16-F10 cells exhibited morphological changes, increased expression of MHCII, CD86, CD80, and production of IL-12 and IFN-γ, suggesting immune activation towards an antitumor profile. These results indicate that the SLNs-AlPc protocol has the potential to improve PDT efficacy by inducing ICD and activating DCs.

Maintaining the vitality and functionality of dental pulp is paramount for tooth integrity, longevity, and homeostasis. Aiming to treat irreversible pulpitis and necrosis, there has been a paradigm shift from conventional root canal treatment towards regenerative endodontic therapy.

This extensive and multipart review presents crucial laboratory and practical issues related to pulp-dentin complex regeneration aimed towards advancing clinical translation of regenerative endodontic therapy and enhancing human life quality.

In this multipart review paper, we first present a panorama of emerging potential tissue engineering strategies for pulp-dentin complex regeneration from cell transplantation and cell homing perspectives, emphasizing the critical regenerative components of stem cells, biomaterials, and conducive microenvironments. Then, this review provides details about current clinically practiced pulp regenerative/reparative approaches, including direct pulp capping and root revascularization, with a specific focus on the remaining hurdles and bright prospects in developing such therapies. Next, special attention was devoted to discussing the innovative biomimetic perspectives opened in establishing functional tissues by employing exosomes and cell aggregates, which will benefit the clinical translation of dental pulp engineering protocols. Finally, we summarize careful consideration that should be given to basic research and clinical applications of regenerative endodontics. In particular, this review article highlights significant challenges associated with residual infection and inflammation and identifies future insightful directions in creating antibacterial and immunomodulatory microenvironments so that clinicians and researchers can comprehensively understand crucial clinical aspects of regenerative endodontic procedures.

Cancer immunotherapy is a revolutionised strategy that strikingly improves cancer treatment in recent years. However, like other therapeutic modalities, immunotherapy faces several challenges and limitations. Many methods have been developed to overcome those limitations; thus, nanomedicine is one of the emerging fields with a highly promising application. Magnetite nanoparticles (MNPs) have long been used for medical applications, for example, as a contrast medium, and are being investigated as a tool for boosting and synergizing the effects of immunotherapy. With known physicochemical properties and the interaction with the surroundings in biological systems, MNPs are used to improve the efficacy of immunotherapy in both cell-based and antibody-based treatment. This chapter reviews and discusses state-of-the-art MNPs as a tool to advance cancer immunotherapy as well as its limitations that need further investigation for a better therapeutic outcome in preclinical and clinical settings.

To evaluate the in vitro and in vivo toxicities of polyethylene glycol-coated gold nanoparticles synthesized using a one-step process.

Gold nanoparticles were prepared via a co-precipitation method using polyethylene glycol, and the synthesis product was characterized. For the in vitro evaluation, a flow cytometry analysis with Annexin V and iodide propidium staining was used to assess cytotoxicity in MG-63 cells labeled with 10, 50, and 100µg/mL of nanoparticle concentration. For the in vivo evaluation, nanoparticles were administered intraperitoneally at a dose of 10mg/kg dose in 10-week-old mice. Toxicity was assessed 24 hours and 7 days after administration via histopathological analysis of various tissues, as well as through renal, hepatic, and hematopoietic evaluations.

Synthesized nanoparticles exhibited different hydrodynamic sizes depending on the medium: 51.27±1.62nm in water and 268.12±28.45nm (0 hour) in culture medium. They demonstrated a maximum absorbance at 520nm and a zeta potential of -8.419mV. Cellular viability exceeded 90%, with less than 3% early apoptosis, 6% late apoptosis, and 1% necrosis across all labeling conditions, indicating minimal cytotoxicity differences. Histopathological analysis highlighted the accumulation of nanoparticles in the mesentery; however, no lesions or visible agglomeration was observed in the remaining tissues. Renal, hepatic, and hematopoietic analyses showed no significant differences at any time point.

Polyethylene glycol-coated gold nanoparticles exhibit extremely low toxicity and high biocompatibility, showing promise for future studies.

Biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) are receiving increasing attention in anti-cancer nanomedicine development not only for targeted cancer chemotherapy, but also for modulation of the tumor microenvironment. We previously reported promising results with cabazitaxel (CBZ) loaded poly(2-ethylbutyl cyanoacrylate) NPs (PEBCA-CBZ NPs) in a patient derived xenograft (PDX) model of triple-negative breast cancer, and this was associated with a decrease in M2 macrophages. The present study aims at comparing two endotoxin-free PACA NP variants (PEBCA and poly(2-ethylhexyl cyanoacrylate); PEHCA), loaded with CBZ and test whether conjugation with folate would improve their effect.

Cytotoxicity assays and cellular uptake of NPs by flow cytometry were performed in different breast cancer cells. Biodistribution and efficacy studies were performed in PDX models of breast cancer. Tumor associated immune cells were analyzed by multiparametric flow cytometry.

In vitro studies showed similar NP-induced cytotoxicity patterns despite difference in early NP internalization. On intravenous injection, the liver cleared the majority of NPs. Efficacy studies in the HBCx39 PDX model demonstrated an enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs. Furthermore, the folate conjugated PEBCA variant did not show any enhanced effects compared with the unconjugated counterpart which might be due to unfavorable orientation of folate on the NPs. Finally, analyses of the immune cell populations in tumors revealed that treatment with drug loaded PEBCA variants affected the myeloid cells, especially macrophages, contributing to an inflammatory, immune activated tumor microenvironment.

We report for the first time, comparative efficacy of PEBCA and PEHCA NP variants in triple negative breast cancer models and show that CBZ-loaded PEBCA NPs exhibit a combined effect on tumor cells and on the tumor associated myeloid compartment, which may boost the anti-tumor response.

Nanoparticles have been employed to elucidate the innate immune cell biology and trace cells accumulating at inflammation sites. Inflammation prompts innate immune cells, the initial responders, to undergo rapid turnover and replenishment within the hematopoietic bone marrow. Yet, we currently lack a precise understanding of how inflammation affects cellular nanoparticle uptake at the level of progenitors of innate immune cells in the hematopoietic marrow. To bridge this gap, we aimed to develop imaging tools to explore the uptake dynamics of fluorescently labeled cross-linked iron oxide nanoparticles in the bone marrow niche under varying degrees of inflammation. The inflammatory models included mice that received intramuscular lipopolysaccharide injections to induce moderate inflammation and streptozotocin-induced diabetic mice with additional intramuscular lipopolysaccharide injections to intensify inflammation. In vivo magnetic resonance imaging (MRI) and fluorescence imaging revealed an elevated level of nanoparticle uptake at the bone marrow as the levels of inflammation increased. The heightened uptake of nanoparticles within the inflamed marrow was attributed to enhanced permeability and retention with increased nanoparticle intake by hematopoietic progenitor cells. Moreover, intravital microscopy showed increased colocalization of nanoparticles within slowly patrolling monocytes in these inflamed hematopoietic marrow niches. Our discoveries unveil a previously unknown role of the inflamed hematopoietic marrow in enhanced storage and rapid deployment of nanoparticles, which can specifically target innate immune cells at their production site during inflammation. These insights underscore the critical function of the hematopoietic bone marrow in distributing iron nanoparticles to innate immune cells during inflammation. Our findings offer diagnostic and prognostic value, identifying the hematopoietic bone marrow as an imaging biomarker for early detection in inflammation imaging, advancing personalized clinical care.

Macrophages are known to depict two major phenotypes: classically activated macrophages (M1), associated with high production of pro-inflammatory cytokines, and alternatively activated macrophages (M2), which present an anti-inflammatory function. A precise control over M1-M2 polarization is a promising strategy in therapeutics to modulate both tissue regeneration and tumor progression processes. However, this is not a simple task as macrophages behave differently depending on the microenvironment. In agreement with this, non-consistent data have been reported regarding macrophages response to magnetic iron oxide nanoparticles (MNPs). To investigate the impact of both tissue microenvironment and MNPs properties on the obtained macrophage responses, single-core (SC) and multi-core (MC) citrate coated MNPs, are synthesized and, afterwards, loaded with a macrophage polarization trigger, IL-4. The developed MNPs are then tested in macrophages subjected to different stimuli. We demonstrate that macrophages treated with low concentrations of MNPs behave differently depending on the polarization stage independently of the concentration of iron. Moreover, we find out that MNPs size and morphology determines the effect of the IL-4 loaded MNPs on M1 macrophages, since IL-4 loaded SC MNPs favor the polarization of M1 macrophages towards M2 phenotype, while IL-4 loaded MC MNPs further stimulate the secretion of pro-inflammatory cytokines.

Fracture healing is a complex interplay of molecular and cellular mechanisms lasting from days to weeks. The inflammatory phase is the first stage of fracture healing and is critical in setting the stage for successful healing. There has been growing interest in exploring the role of the immune system and novel therapeutic strategies, such as nanoparticle drug delivery systems in enhancing fracture healing. Advancements in nanotechnology have revolutionized drug delivery systems to the extent that they can modulate immune response during fracture healing by leveraging unique physiochemical properties. Therefore, understanding the intricate interactions between nanoparticle-based drug delivery systems and the immune response, specifically macrophages, is essential for therapeutic efficacy. This review provides a comprehensive overview of the relationship between the immune system and nanoparticles during fracture healing. Specifically, we highlight the influence of nanoparticle characteristics, such as size, surface properties, and composition, on macrophage activation, polarization, and subsequent immune responses. IMPACT STATEMENT: This review provides valuable insights into the interplay between fracture healing, the immune system, and nanoparticle-based drug delivery systems. Understanding nanoparticle-macrophage interactions can advance the development of innovative therapeutic approaches to enhance fracture healing, improve patient outcomes, and pave the way for advancements in regenerative medicine.

Multipollutant approach is a breakthrough in up-to-date environmental quality and health risk estimation. Both mercury and carbonaceous air particulate are hazardous neurotoxicants. Here, the ability of carbonaceous air particulate simulants, i.e. carbon dots obtained by heating of organics, and nanodiamonds, to influence Hg2+-induced neurotoxicity was monitored using biological system, i.e. presynaptic rat cortex nerve terminals. Using HgCl2 and classical reducing/chelating agents, an adequate synaptic parameter, i.e. the extracellular level of key excitatory neurotransmitter L-[14C]glutamate, was selected for further analysis. HgCl2 starting from 5 µM caused an acute and concentration-dependent increase in the extracellular L-[14C]glutamate level in nerve terminals. Combined application of Hg2+ and carbon dots from heating of citric acid/urea showed that this simulant was able to mitigate in an acute manner excitotoxic Hg2+-induced increase in the extracellular L-[14C]glutamate level in nerve terminals by 37%. These carbon dots and Hg2+ acted as a complex in nerve terminals that was confirmed with fluorimetric data on Hg2+-induced changes in their spectroscopic features. Nanodiamonds and carbon dots from β-alanine were not able to mitigate a Hg2+-induced increase in the extracellular L-[14C]glutamate level in nerve terminals. Developed approach can be applicable for monitoring capability of different particles/compounds to have Hg2+-chelating signs in the biological systems. Therefore, among testing simulants, the only carbon dots from citric acid/urea were able to mitigate acute Hg2+-induced neurotoxicity in nerve terminals, thereby showing a variety of effects of carbonaceous airborne particulate in situ and its potential to interfere and modulate Hg2+-associated health hazard.

This study aimed to investigate the effects of nanoparticles on macrophage polarization and their subsequent influence on post-tumorigenic behavior. Initially, seven different nanoparticles were applied to macrophages, and Zn-Ni-FeO (100 nm) and palladium nanoparticles (PdNPs, ∼25 nm) were found to induce M1-polarization in macrophages. A co-culture experiment was then conducted to examine the effects of macrophages on MCF-7 breast cancer micro-tissues. The M2-macrophages promoted tumor proliferation, while M1- and PdNPs-induced macrophages showed anti-tumor effects by suppressing cell proliferation. To reveal the mechanisms of effect, exosomes isolated from M1 (M1-Exo), M0 (M0-Exo), M2 (M2-Exo), and PdNPs-induced (PdNPs-Exo) macrophages were applied to the heterotypic tumor micro-tissues including MCF-7, human umbilical vein endothelial cells (HUVECs), and primary human dermal fibroblasts (phDFs). M2-Exo was seen to promote the migration of cancer cells and induce epithelial-mesenchymal transition (EMT), while M1-Exo suppressed these behaviors. PdNPs-Exo was effective in suppressing the aggressive nature of breast cancer cells similar to M1-Exo, moreover, the efficacy of 5-fluorouracil (5-FU) was increased in combination with PdNPs-Exo in both MCF-7 and heterotypic micro-tissues. In conclusion, PdNPs-Exo has potential anti-tumor effects, can be used as a combination therapy to enhance the efficacy of anti-cancer drugs, as well as innovative implants for breast cancer treatment.

Polyelectrolyte capsules (PCs) are a promising tool for anticancer drug delivery and tumor targeting. Surface functionalization of PCs with antibodies is widely used for providing their specific interactions with cancer cells. The efficiency of PC-based targeted delivery systems can be affected by the cellular heterogeneity of the tumor, particularly by the presence of tumor-associated macrophages. We used human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells in either monoculture or coculture to analyze the targeting capacity and internalization efficiency of PCs with a mean size of 1.03 ± 0.11 μm. The PCs were functionalized with the monoclonal antibody cetuximab targeting the human epidermal growth factor receptor (EGFR). We have shown that surface functionalization of the PCs with cetuximab ensures a specific interaction with EGFR-expressing cancer cells and promotes capsule internalization. In monoculture, the macrophages derived from human leukemia monocytic cells have been found to internalize both nonfunctionalized PCs and cetuximab-functionalized PCs (Cet-PCs) more intensely compared to epidermoid carcinoma cells. The internalization of Cet-PCs by cancer cells is mediated by lipid rafts of the cell membrane, whereas the PC internalization by macrophages is only slightly influenced by lipid rafts. Experiments with a coculture of human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells have shown that Cet-PCs preferentially interact with cancer cells, which are subsequently attacked by macrophages. These data can be used to further improve the strategy of PC functionalization for targeted delivery, with the cellular heterogeneity of the tumor microenvironment taken into consideration.

Macrophages play a pivotal role in tumor immunity. We report that reprogramming of macrophages to tumor-associated macrophages (TAMs) promotes the secretion of exosomes. Mechanistically, increased exosome secretion is driven by MADD, which is phosphorylated by Akt upon TAM induction and activates Rab27a. TAM exosomes carry high levels of programmed death-ligand 1 (PD-L1) and potently suppress the proliferation and function of CD8+ T cells. Analysis of patient melanoma tissues indicates that TAM exosomes contribute significantly to CD8+ T cell suppression. Single-cell RNA sequencing analysis showed that exosome-related genes are highly expressed in macrophages in melanoma; TAM-specific RAB27A expression inversely correlates with CD8+ T cell infiltration. In a murine melanoma model, lipid nanoparticle delivery of small interfering RNAs (siRNAs) targeting macrophage RAB27A led to better T cell activation and sensitized tumors to anti-programmed cell death protein 1 (PD-1) treatment. Our study demonstrates tumors use TAM exosomes to combat CD8 T cells and suggests targeting TAM exosomes as a potential strategy to improve immunotherapies.

In the context of glioblastoma (GBM), hypoxia and inflammation are two main players of the tumor microenvironment. Hypoxia stimulates various features involves in tumor growth and also maintains a specific environment that favors protumor macrophages. Therefore, targeting hypoxia could potentially restore an anti-tumor M1 phenotype in macrophages. Besides, iron demonstrated its capacity to stimulate the polarization of macrophages towards an M1-like phenotype. In this paper we took advantages of microporous nanoparticles to co-deliver both oxygen and iron to bone marrow derived macrophages (BMDM) enabling the investigation of changes in polarization status and proteomic profiles. The nanoparticles were used in two in vivo models of glioblastoma, specifically, in both immunodeficient and immunocompetent settings. Our in vitro findings revealed that iron doped nanoparticles, saturated with oxygen were deemed safe for macrophages but did not demonstrate the capacity to change the M1 or M2 phenotypes. However, these nanoparticles induced some changes in proteomics pathways. The present study reports on in vivo experimentation that revealed the effects of nanoparticles on the hypoxic fraction, tumor volume, and macrophage phenotype in a GBM model. The findings indicated that the presence of nanoparticles led to a reduction in the hypoxic fraction in one of the GBM models, while no significant changes were observed in the tumor volume or macrophage phenotype. The present data showed that nanoparticles possess the capability of delivering both oxygen and iron to macrophages; though, they do not possess the ability to effectively repolarize M2 macrophages. Such strategies could be used in conjunction with other potent molecules to avoid M1 macrophages to inevitably differentiate to M2 macrophages.

Macrophage-assisted immunomodulation is an alternative strategy in tissue engineering, wherein the interplay between pro-inflammatory and anti-inflammatory macrophage cells and body cells determines the fate of healing or inflammation. Although several reports have demonstrated that tissue regeneration depends on spatial and temporal regulation of the biophysical or biochemical microenvironment of the biomaterial, the underlying molecular mechanism behind immunomodulation is still under consideration for developing immunomodulatory scaffolds. Currently, most fabricated immunomodulatory platforms reported in the literature show regenerative capabilities of a particular tissue, for example, endogenous tissue (e.g., bone, muscle, heart, kidney, and lungs) or exogenous tissue (e.g., skin and eye). In this review, we briefly introduced the necessity of the 3D immunomodulatory scaffolds and nanomaterials, focusing on material properties and their interaction with macrophages for general readers. This review also provides a comprehensive summary of macrophage origin and taxonomy, their diverse functions, and various signal transduction pathways during biomaterial-macrophage interaction, which is particularly helpful for material scientists and clinicians for developing next-generation immunomodulatory scaffolds. From a clinical standpoint, we briefly discussed the role of 3D biomaterial scaffolds and/or nanomaterial composites for macrophage-assisted tissue engineering with a special focus on bone and associated tissues. Finally, a summary with expert opinion is presented to address the challenges and future necessity of 3D bioprinted immunomodulatory materials for tissue engineering.

Skeletal muscle disease severity can often progress asymmetrically across muscle groups and heterogeneously within tissues. An example is Duchenne Muscular Dystrophy (DMD) in which lack of dystrophin results in devastating skeletal muscle wasting in some muscles whereas others are spared or undergo hypertrophy. An efficient, non-invasive approach to identify sites of asymmetry and degenerative lesions could enable better patient monitoring and therapeutic targeting of disease. In this study, we utilized a versatile intravenously injectable mesoporous silica nanoparticle (MSNP) based nanocarrier system to explore mechanisms of biodistribution in skeletal muscle of mdx mouse models of DMD including wildtype, dystrophic, and severely dystrophic mice. Moreover, MSNPs could be imaged in live mice and whole muscle tissues enabling investigation of how biodistribution is altered by different types of muscle pathology such as inflammation or fibrosis. We found MSNPs were tenfold more likely to aggregate within select mdx muscles relative to wild type, such as gastrocnemius and quadriceps. This was accompanied by decreased biodistribution in off-target organs. We found the greatest factor affecting preferential delivery was the regenerative state of the dystrophic skeletal muscle with the highest MSNP abundance coinciding with the regions showing the highest level of embryonic myosin staining and intramuscular macrophage uptake. To demonstrate, muscle regeneration regulated MSNP distribution, we experimentally induced regeneration using barium chloride which resulted in a threefold increase of intravenously injected MSNPs to sites of regeneration 7 days after injury. These discoveries provide the first evidence that nanoparticles have selective biodistribution to skeletal muscle in DMD to areas of active regeneration and that nanoparticles could enable diagnostic and selective drug delivery in DMD skeletal muscle.

Sarcoptes scabiei (S. scabiei) endangers human and other mammalian health. There has been limited research into S. scabiei pathogenic mechanisms and the immunological interaction between S. scabiei and hosts. Galectins have critical roles in biological processes such as cell adhesion, signal transduction, and immune response mediation. Galectins of S. scabiei (SsGalectins) were cloned, expressed, and identified, and their transcriptional levels in S. scabiei were measured at various developmental stages. Fluorescent tissue localization was performed on SsGalectins of S. scabiei and scabies skin. A mouse AD model was constructed to evaluate the effect of rSsGalectins on skin pathogenic changes. Quantitative polymerase chain reaction and enzyme-linked immunoassay were used to identify macrophage polarization-related components and investigate the immunoregulatory effect of rSsGalectins on mouse macrophages. The results demonstrated that the S. scabiei infection causes macrophage infiltration in the scabies skin. The rSsGalectins displayed strong reactogenicity, and distinct genes of the SsGalectins were differently expressed in different developmental stages of S. scabiei. Fluorescence tissue localization revealed that the SsGalectins were mainly in the mouthparts, intestines, and body surface. Additionally, S. scabiei could secrete SsGalectins into the infected skin, proving that SsGalectins were excretion and secretion proteins of S. scabiei. In the mouse atopic dermatitis model, cutaneous macrophage infiltration and inflammation increase after rSsGalectins injection. Simultaneously, when rSsGalectins acted on bone marrow-derived macrophages, M1 macrophage-related polarization factors IL-1β, IL-6, and inducible nitric oxide synthase all increased, demonstrating that rSsGalectins can induce M1 polarization and produce pro-inflammatory cytokines. In conclusion, the SsGalectins are involved in the pathogenic process of S. scabiei by regulating the polarization of host macrophages to the M1 type when S. scabiei invade the host and promoting the incidence and development of the host's inflammatory response. This study offers fresh light on the pathogenic process of scabies mites, investigates the immunological interaction mechanism between S. scabiei and the host, and offers new insights into S. scabiei prevention and therapy.

Immunotherapy for immune response has ushered in a new era of cancer treatment. In recent years, new immunotherapeutic agents have been introduced into clinical trials and even approved for marketing. However, the widespread use of immunotherapeutic agents faces an unavoidable challenge: immunotherapy does not work at all for some patients, or has good efficacy in the initial phase, but immunotherapy resistance develops within a short period of time, and immunotherapy can also cause serious adverse effects such as autoimmune inflammation and non-specific inflammation. How to enable patients to overcome drug resistance, reduce the toxic side effects of drugs, enhance patient compliance and improve patient survival has become a problem that clinicians have to face. The advent of nanotechnology provides an encouraging platform for immunotherapy. It can not only improve the bioavailability and stability of drugs and reduce toxic side effects, but also reduce resistance to immunotherapy. Here, we discuss these research advances and discuss potential challenges and future directions.

Macrophages play a critical role in the immune response due to their ability to recognize and remove pathogens, as well as present antigens, which are involved in inflammation, but they are also one of the most abundant immune cell populations present in the tumor microenvironment. In recent years, macrophages have become promising cellular carriers for drug and nanoparticle delivery to the tumor microenvironment, mainly due to their natural properties such as biocompatibility, degradability, lack of immunogenicity, long half-life in circulation, crossing biological barriers, and the possibility of migration and accumulation at a site of inflammation such as a tumor. For the effectiveness of this therapeutic strategy, known as "Trojan horse", it is important that the nanoparticles engulfed by macrophages do not affect their proper functioning. In our review, we discussed how the size, shape, chemical and mechanical properties of nanoparticles influence their internalization by macrophages. In addition, we described the promising research utilizing macrophages, their cell membranes and macrophage-derived exosomes as drug carriers in anticancer therapy. As a prospect of the wider use of this therapeutic strategy, we postulate its future application in boron delivery to the tumor environment in boron neutron capture therapy.

New therapeutic strategies are required in cancer therapy. Considering the prominent role of tumor-associated macrophages (TAMs) in the development and progression of cancer, the re-education of TAMs in the tumor microenvironment (TME) could represent a potential approach for cancer immunotherapy. TAMs display an irregular unfolded protein response (UPR) in their endoplasmic reticulum (ER) to endure environmental stress and ensure anti-cancer immunity. Therefore, nanotechnology could be an attractive tool to modulate the UPR in TAMs, providing an alternative strategy for TAM-targeted repolarization therapy. Herein, we developed and tested polydopamine-coupled magnetite nanoparticles (PDA-MNPs) functionalized with small interfering RNAs (siRNA) to downregulate the protein kinase R (PKR)-like ER kinase (PERK) expression in TAM-like macrophages derived from murine peritoneal exudate (PEMs). After the evaluation of the cytocompatibility, the cellular uptake, and the gene silencing efficiency of PDA-MNPs/siPERK in PEMs, we analyzed their ability to re-polarize in vitro these macrophages from M2 to the M1 inflammatory anti-tumor phenotype. Our results indicate that PDA-MNPs, with their magnetic and immunomodulator features, are cytocompatible and able to re-educate TAMs toward the M1 phenotype by PERK inhibition, a UPR effector contributing to TAM metabolic adaptation. These findings can provide a novel strategy for the development of new tumor immunotherapies in vivo.

Reprogramming tumor-associated macrophages (TAMs) has emerged as a promising strategy in cancer immunotherapy. Targeted therapeutics integrating multiple functions to fully leverage the antitumor immune functions of macrophages without affecting systemic or tissue-resident macrophages are crucial for TAM reprogramming. Herein, by integrating molecular imprinting and nanotechnology, we rationally designed and engineered an unprecedented nanocoordinator for targeted remolding of TAMs to fully leverage the antitumor efficacy of macrophages by inducing a cascade effect. The nanocoordinator features a magnetic iron oxide nanoinner core and sialic acid-imprinted shell. Intravenously administered into systemic circulation, the nanocoordinator can rapidly accumulate at the tumor site in response to an external magnet. Then, by specifically binding to sialic acid overexpressed on tumor cells, the nanocoordinator anchors at the tumor site with prolonged retention time. Via binding with the nanocoordinator, tumor cells are tagged with a foreign substance, which promotes the intrinsic phagocytosis of macrophages. Subsequently, the nanocoordinator taken up by macrophages effectively promotes the polarization of macrophages toward the M1 phenotype, thus activating the immunotherapeutic efficacy of macrophages. Synergized by the cascade effect, this nanocoordinator effectively harnesses TAMs for macrophage-mediated immunotherapy. This study offers new TAM-targeted therapeutics that allows us to fully leverage the antitumor immune functions of macrophages without affecting the normal tissue.

The current standard for treating irreversibly damaged dental pulp is root canal therapy, which involves complete removal and debridement of the pulp space and filling with an inert biomaterial. A regenerative approach to treating diseased dental pulp may allow for complete healing of the native tooth structure and enhance the long-term outcome of once-necrotic teeth. The aim of this paper is, therefore, to highlight the current state of dental pulp tissue engineering and immunomodulatory biomaterials properties, identifying exciting opportunities for their synergy in developing next-generation biomaterials-driven technologies.

An overview of the inflammatory process focusing on immune responses of the dental pulp, followed by periapical and periodontal tissue inflammation are elaborated. Then, the most recent advances in treating infection-induced inflammatory oral diseases, focusing on biocompatible materials with immunomodulatory properties are discussed. Of note, we highlight some of the most used modifications in biomaterials' surface, or content/drug incorporation focused on immunomodulation based on an extensive literature search over the last decade.

We provide the readers with a critical summary of recent advances in immunomodulation related to pulpal, periapical, and periodontal diseases while bringing light to tissue engineering strategies focusing on healing and regenerating multiple tissue types.

Significant advances have been made in developing biomaterials that take advantage of the host's immune system to guide a specific regenerative outcome. Biomaterials that efficiently and predictably modulate cells in the dental pulp complex hold significant clinical promise for improving standards of care compared to endodontic root canal therapy.

Macrophage polarization is an essential process involved in immune regulation. In response to different microenvironmental stimulation, macrophages polarize into cells with different phenotypes and functions, most typically M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Iron-based nanoparticles have been widely explored and reported to regulate macrophage polarization for various biomedical applications. However, the influence factors and modulation mechanisms behind are complicated and not clear. In this review, we systemically summarized different iron-based nanoparticles that regulate macrophage polarization and function and discussed the influence factors and mechanisms underlying the modulation process. This review aims to deepen the understanding of the modulation of macrophage polarization by iron-based nanoparticles and expects to provide evidence and guidance for subsequent design and application of iron-based nanoparticles with specific macrophage modulation functions.

Macrophages, the major component of the mononuclear phagocyte system, uptake and clear systemically administered nanoparticles (NPs). Therefore, leveraging macrophages as a druggable target may be advantageous to enhance NP-mediated drug delivery. Despite many studies focused on NP-cell interactions, NP-mediated macrophage polarization mechanisms are still poorly understood. This work aimed to explore the effect of NP physicochemical parameters (size and charge) on macrophage polarization. Upon exposure to biological fluids, proteins rapidly adsorb to NPs and form protein coronas. To this end, we hypothesized that NP protein coronas govern NP-macrophage interactions, uptake, and subsequent macrophage polarization. To test this hypothesis, model polystyrene NPs with various charges and sizes, as well as NPs relevant to drug delivery, were utilized. Data suggest that cationic NPs potentiate both M1 and M2 macrophage markers, while anionic NPs promote M1-to-M2 polarization. Additionally, anionic polystyrene nanoparticles (APNs) of 50 nm exhibit the greatest influence on M2 polarization. Proteomics was pursued to further understand the effect of NPs physicochemical parameters on protein corona, which revealed unique protein patterns based on NP charge and size. Several proteins impacting M1 and M2 macrophage polarization were identified within cationic polystyrene nanoparticles (CPNs) corona, while APNs corona included fewer M1 but more M2-promoting proteins. Nevertheless, size impacts protein corona abundance but not identities. Altogether, protein corona identities varied based on NP surface charge and correlated to dramatic differences in macrophage polarization. In contrast, NP size differentially impacts macrophage polarization, which is dominated by NP uptake level rather than protein corona. In this work, specific corona proteins were identified as a function of NP physicochemical properties. These proteins are correlated to specific macrophage polarization programs and may provide design principles for developing macrophage-mediated NP drug delivery systems.

Nanocellulose application has been increasing owing to its appealing physicochemical properties. Monitoring of the crystallinity, surface topography, and reactivity of this high-aspect-ratio nanomaterial is crucial for efficient tissue engineering. Controlling macrophage polarization phenotype remains a challenge in regenerative medicine and tissue engineering. Herein, we monitored the effects of shape-regulated (rod and spherical) nanocellulose on the macrophage modulatory potential of RAW 246.7 cells in vitro. Spherical nanocellulose (s-NC) exhibited higher thermal stability and biocompatibility than rod nanocellulose. Macrophage polarization was profoundly affected by nanocellulose topography and incubation period. M2 polarization was observed in vitro after 1 day of treatment with s-NC, followed by M1 polarization after treatment for longer periods. Transcriptome analysis similarly revealed that M1 polarization was dominant after 1 day h of incubation with both nanocellulose types. These findings demonstrate that macrophage polarization can be controlled by selecting suitable nanocellulose shape and incubation time for desired applications.

The characteristics of global prevalence and high recurrence of bladder cancer has led numerous efforts to develop new treatments. The spontaneous voiding and degradation of the chemodrug hamper the efficacy and effectiveness of intravesical chemotherapy following tumor resection. Herein, the externally thiolated hollow mesoporous silica nanoparticles (MSN-SH(E)) is fabricated to serve as a platform for improved bladder intravesical therapy. Enhanced mucoadhesive effect of the thiolated nanovector is confirmed with porcine bladder. The permeation-enhancing effect is also verified, and a fragmented distribution pattern of a tight junction protein, claudin-4, indicates the opening of tight junction. Moreover, MSN-SH(E)-associated reprogramming of M2 macrophages to M1-like phenotype is observed in vitro. The antitumor activity of the mitomycin C (MMC)-loaded nanovector (MMC@MSN-SH(E)) is more effective than that of MMC alone in both in vitro and in vivo. In addition, IHC staining is used to analyze IFN-γ, TGF-β1, and TNF-α. These observations substantiated the significance of MMC@MSN-SH(E) in promoting anticancer activity, holding the great potential for being used in intravesical therapy for non-muscle invasive bladder cancer (NMIBC) due to its mucoadhesivity, enhanced permeation, immunomodulation, and prolonged and very efficient drug exposure.

In recent decades, immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T) therapy are two milestone achievements in clinical immunotherapy. However, both show limited efficacies in most solid neoplasms, which necessitates the exploration of new immunotherapeutic modalities. The failure of CAR-T and immune checkpoint blockade in several solid neoplasms is attributed to multiple factors, including low antigenicity of tumor cells, low infiltration of effector T cells, and diverse mechanisms of immunosuppression in the tumor microenvironment. New adoptive cell therapies have been attempted for solid neoplasms, including TCR-T, CAR-natural killer cells (CAR-NK), and CAR-macrophages (CAR-M). Compared to CAR-T, these new adoptive cell therapies have certain advantages in treating solid neoplasms. In this review, we summarized the 40-year evolution of adoptive cell therapies, then focused on the advances of TCR-T, CAR-NK, and CAR-M in solid neoplasms and discussed their potential clinical applications.