Nanomedicine was previously regarded as a promising solution in the battle against cancer. Over the past few decades, extensive research has been conducted to exploit nanomedicine for overcoming tumors. Unfortunately, despite these efforts, nanomedicine has not yet demonstrated its ability to cure tumors, and the research on nanomedicine has reached a bottleneck. For a significant period of time, drug delivery strategies have primarily focused on targeting nanomedicine delivery to tumors while neglecting its redistribution within solid tumors. The uneven distribution of nanomedicine within solid tumors results in limited therapeutic effects on most tumor cells and significantly hampers the efficiency of drug delivery and treatment outcomes. Therefore, this review discusses the challenges faced by nanomedicine in penetrating solid tumors and provides an overview of current nanotechnology strategies (alleviating penetration resistance, size regulation, tumor cell transport, and nanomotors) that facilitate enhanced penetration of nanomedicine into solid tumors. Additionally, we discussed the potential role of nanobionics in promoting effective penetration of nanomedicine.

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with limited success in traditional therapies due to the fibrotic, immunosuppressive, pro-metastatic tumor microenvironment (TME), which collectively impede the drug accumulation and accelerate the tumor progression. In this work, we developed a PDAC-customized nutrient-mimicking reconstituted high-density lipoprotein (rHDL) capable of efficiently co-encapsulate versatile TME regulating cannabidiol and cytotoxic gemcitabine to simultaneously reprogram TME while suppressing PDAC progression. Specifically, a small-sized, nutrient-like rHDL was constructed to realize deep PDAC parenchyma penetration and efficient intra-tumoral uptake. Next, natural herbal compound cannabidiol was screened and incorporated into rHDL to regulate TME via attenuating fibrosis, reliving immunosuppression and mitigating metastatic tendency. At last, gemcitabine, the PDAC gold standard first-line therapy was co-delivered by the PDAC-customized rHDL to overcome drug resistance and amplify its PDAC suppression. Our findings demonstrate the feasibility of an integrated multi-stage TME regulation strategy for improved PDAC therapy, and might represent a modality in promoting chemotherapy against PDAC.

Actively targeted nanoparticle systems have the potential to improve delivery to tumors over untargeted systems however the design rules to achieve this have not been fully elucidated. A HER2-targeted polymer drug delivery system composed of a 32-arm star polymer (SD) conjugated with the TOP1 inhibitor molecule SN-38, with a trastuzumab antigen binding fragment (HER2-Fab), has been used to target cancer cells overexpressing this receptor. The HER2-Fab was attached to the SD at two different densities (average of 1 or 3 Fabs per star polymer) and compared to the native star polymer without Fab. In vitro experimentation showed that both the targeted star polymers (HER2-SDs) had better binding and uptake in HER2-positive cell lines (SK-BR3 and HEK293) compared to the non-targeted SD. In vivo biodistribution studies showed enhanced accumulation of HER2-targeted SDs in tumors, but not normal tissues, particularly at the later (96 h post-dose) timepoint. The HER2-SDs demonstrated increased localization with tumor cells rather than in stromal regions, greater penetration into the tumor core and a more homogenous distribution in the tumor section than the untargeted SD. The targeted star polymer conjugated to SN-38 was tested for anti-tumor activity in a HER2-positive gastric cancer xenograft in mice and showed significantly greater efficacy compared to untargeted SDs.

Bone marrow (BM) has roles in health and disease, so systemically administered nanocarriers (NCs) targeting or avoiding BM are desirable. While the hydrodynamic diameter of NCs can be tuned to target or avoid various organs, the size dependence of extravasation from BM vessels is unknown. To clarify the size dependence of passive transvascular transport in the BM, we performed vessel permeability measurements in murine calvaria using confocal fluorescent microscopy with fluorescently labeled dextrans, albumin, and polymeric micelles as model probes. Unexpectedly, we found the permeability of BM vessels to macromolecules decreases with increasing hydrodynamic diameter between 4 nm and 32 nm. We modeled this permeability data with mathematical models to predict an effective pore size for sinusoids of 47 nm and non-sinusoids of 37 nm, with estimated maximum pore sizes of 61 nm and 53 nm, respectively. Finally, we tested these model predictions by demonstrating that the extravasation of 70 nm polymeric micelles, which are larger than the estimated maximum pore size, is hindered relative to 30 nm polymeric micelles. These results establish design criteria for controlling NC hydrodynamic diameter towards modulating delivery to BM.

Nanocarriers can improve the therapeutic efficiency of small molecule immunomodulators or inhibitors, which is important for immunotherapy of liver diseases or cancer. Macromolecular protein carriers, such as human serum albumin (HSA), could provide better penetration compared to large nanoparticles (>50 nm) but are hampered by systemic biodistribution. To overcome these limitations, inspired by the natural glycogen structure, we have designed the HSA nanocarrier (<40 nm) consisting of multiple trimannose (TM) ligands attached to the protein surface, to target mannose or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptors in immune cells or immunological organs such as the liver. Capitalizing on the chemical reactivity of different amino acids present in HSA, we have incorporated multiple copies of a cargo relevant for immunotherapy, i.e. the toll-like receptor (TLR) 7/8 agonist. The resulting TM-HSA conjugates exhibit excellent and specific uptake ex vivo in various immune cells and liver-specific uptake in vivo, opening access to protein nanocarriers with rapid and efficient in vivo targeting with great potential for immune-related diseases.

Advanced prostate cancer is hassled by relapse and metastasis that are closely associated with cancer stem cells (CSCs). Here, we present micellar indocyanine green and napabucasin (mICG-Nap) that co-ablates cancer cells and CSCs via photothermal therapy (PTT) for the treatment of prostate tumor. mICG-Nap with stable loading of both drugs and favorable size effectively reduced CSC population in RM1-PSMA murine prostate cancer cells and inhibited tumor spheroid formation. mICG-Nap showed an enhanced photothermal effect compared with free ICG and eliminated tumor spheroids under near-infrared (NIR) irradiation. The efficacy of mICG-Nap was further enhanced by decorating with Acupa ligand, which targets to RM1-PSMA cells and tumors via PSMA receptor. The enhanced tumor cell uptake of Acupa-mICG-Nap led to significant survival benefits in both subcutaneous RM1-PSMA tumor models and postoperative models. The tumor analyses demonstrated clear downregulation of CSC-related biomarkers such as OCT4, SOX2, CD133 and pSTAT3 as well as PSMA by Acupa-mICG-Nap. Rational formulated micellar indocyanine green and napabucasin plus NIR appears as an appealing strategy to co-ablate cancer cells and CSCs with rapid tumor de-bulking yet no recurrence.

To develop a nano-immunotherapy system combining autophagy inhibition and innate immune activation to reverse the immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC).

The pH-responsive polymer PC7A was utilized to co-deliver the autophagy inhibitor chloroquine (CQ) and the STING agonist cyclic diguanylate (CDG), forming the CQCP nanosystem. In vitro and in vivo experiments evaluated autophagy inhibition, MHC-I expression, dendritic cell activation, tumor infiltration of lymphocytes, and survival in PDAC-bearing mice.

CQCP enhanced MHC-I expression on PDAC cells by 2.1-fold (p < 0.001) and increased activated dendritic cells (CD86+/CD40+) by 3.5-fold (p < 0.01) in the TME. Tumor-infiltrating CD8+ T cells rose by 42.6% (p < 0.001), and systemic immune activation in peripheral lymphoid tissues was observed. CQCP achieved an 86% survival rate in tumor-bearing mice, significantly outperforming monotherapies or free drug combinations.

The CQCP system synergistically reverses PDAC immunosuppression by restoring antigen presentation and activating innate immunity. This dual-targeted strategy demonstrates robust antitumor efficacy and offers a promising immunotherapy approach for PDAC.

Macromolecular drugs, such as proteins and nucleic acids, play a pivotal role in treating refractory diseases and hold significant promise in the growing pharmaceutical market. However, without efficient delivery systems, macromolecular drugs are highly susceptible to rapid biodegradation or systemic clearance, underscoring the need for advanced delivery strategies for clinical translation. A major challenge lies in their limited tissue penetration due to large molecular weight and size, which has recently garnered significant attention as it often leads to therapeutic failure or the emergence of resistance. In this review, we first outline the biological barriers limiting macromolecular tissue penetration, then explore the inherent permeation mechanisms of biomacromolecules in biological systems. We then highlight delivery strategies aimed at enhancing the tissue penetration of macromolecular therapeutics, with a particular focus on tissue-adaptive and tissue-remodeling delivery platforms. Finally, we provide a concise perspective on future research directions in deep tissue penetration for biomacromolecules. This review offers a comprehensive summary of recent advancements and presents critical insights into optimizing the therapeutic efficacy of macromolecular drugs.

This study successfully constructs a tumor-targeting α-lipoic acid-loaded hollow mesoporous prussian blue nanozyme (AHPRzyme) for targeted therapy of nasopharyngeal carcinoma in mice. In these nanozymes, Arg-Gly-Asp (RGD) acts as a targeting ligand, enabling effective targeting of tumor cells. Additionally, AHPRzyme exhibits multiple anti-tumor mechanisms: ① The prussian blue nanozymes in AHPRzyme have catalase (CAT) activity, which decomposes H2O2 in human nasopharyngeal carcinoma CEN2 cells into non-toxic H2O, reducing H2O2 levels and minimizing damage to normal cells. The released O2 helps alleviate the hypoxic environment of the tumor, inhibiting lactate production due to hypoxia and consequently suppressing tumor growth. ② The prussian blue nanozymes also have peroxidase (POD) activity, which catalyzes H2O2 in tumor cells to generate ·OH, a reactive oxygen species, leading to tumor cell apoptosis. ③ The α-lipoic acid structure in AHPRzyme contains disulfide bonds that react with GSH, depleting excess glutathione (GSH) in tumor cells, disrupting the oxidative stress balance within the cells, and making them more sensitive to reactive oxygen species, thereby increasing tumor cell apoptosis. In summary, AHPRzyme can inhibit tumor cell growth and promote tumor cell apoptosis by improving the tumor microenvironment, achieving the goal of anti-nasopharyngeal carcinoma therapy.

The intricate interplay between nanomaterials and the biological molecules has garnered considerable interest in understanding the dynamics of protein corona formation at the nano-bio interface. This review provides an in-depth exploration of protein-nanoparticle interactions, elucidating their structural dynamics and thermodynamics at the nano-Bio interface and further on emphasizing its formation, composition, challenges, and applications in the biomedical and nanotechnological domains, such as drug delivery, theranostics, and the translational medicine. We delve the nuanced mechanisms governing protein corona formation on nanoparticle surfaces, highlighting the influence of nanoparticle and biological factors, and review the impact of corona formation on the biological identity and functionality of nanoparticles. Notably, emerging applications of artificial intelligence and machine learning have begun to revolutionize this field, enabling accurate prediction of corona composition and related biological outcomes. These tools not only enhance efficiency over traditional experimental methods but also help decode complex protein-nanoparticle interaction patterns, offering new insights into corona-driven cellular responses and disease diagnostics. Additionally, it discusses recent advancements in the field of protein corona, particularly in translational nanomedicine and associated applications entailing current and future strategies which are aimed at mitigating the adverse effects of protein-nanoparticle interactions at the biological interface, for tailoring the protein coronas by engineering of the nanomaterials. This comprehensive assessment from chemical, technological, and biological aspects serves as a guiding beacon for the development of future nanomedicine, enabling the more effective emulation of the biological milieu and the design of protein-NP systems for enhanced biomedical applications.

The insufficient enrichment and penetration of sonosensitizers in the tumor site hamper the antitumor efficiency of sonodynamic therapy (SDT). Herein, tumor-acidity and photothermal controlled nanosystems (NTTD), which coloaded a new type of sonosensitizers, Na3TiF6 NPs and second near-infrared (NIR-II) emissive AIEgen (T1), have been developed to achieve highly efficient SDT/photothermal therapy (PTT) in deep-seated tumors. On one hand, NTTD includes ultrasmall Na3TiF6 NPs with increased oxygen vacancies, narrow bandgap (2.82 eV) and preferrable absorption capability of H2O and O2 molecules, guaranteeing powerful generation of reactive oxygen species (ROS) under US stimulation. On the other hand, with the assistance of the acidic/photothermal responses and deep penetrated NIR-II fluorescence imaging (up to 7 mm), NTTD undergo in situ "two-step" size transformation to achieve enhanced retention and penetration of sonosensitizers in tumor area with high spatiotemporal controllability. In 4T1 tumor model, compared to passive targeting participated NTT group, NTTD elongated the tumor retention time to 60 h and revealed enhanced imaging signal (∼2.4 fold). Further photoirradiation of NTTD assisted ∼4.5-fold enhancement of penetration ability. SDT/PTT synergies have evoked significant ROS generation and tumor inhibition rate of 75.2 % in vivo. This study presents an innovative strategy to exploit novel nano-sonosensitizers with precisely improved tumor accumulation and penetration.

Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Transcatheter arterial chemoembolization has become a common treatment modality for some patients with unresectable advanced HCC. Since the introduction of nanomaterials in 1974, their use in various fields has evolved rapidly. In medical applications, nanomaterials can serve as carriers for the delivery of chemotherapeutic drugs to tumour tissues. Additionally, nanomaterials have potential for in vivo tumour imaging. This article covers the properties and uses of several kinds of nanomaterials, focusing on their use in transcatheter arterial chemoembolization for HCC treatment. This paper also discusses the limitations currently associated with the use of nanomaterials.

The development of anti-tumor nanomedicines grapples with the critical challenge of achieving sustained retention and massive intratumoral distributions of chemotherapeutics. Herein, we attempted multifaceted prodrug nanomedicine with precise spatiotemporal responsiveness, integrating dual prodrugs-redox-responsive SN38 and pH-responsive thrombin and ensuring drug release coinciding with the striking tumor acidity and reductive stress, while its spatial selectivity is directed by the overexpression of integrins on cancerous cells. Most importantly, the thrombin component induces vascular occlusion within tumors, leading to normalization of the elevated interstitial fluid pressure and promoting accumulation of chemotherapeutic agents. This approach not only facilitates the massive intratumoral distribution of the nanomedicine but also ensures sustained retention of SN38 within the tumor microenvironment, thereby augmenting the cytotoxic potencies. Of note, the advanced mass spectrum mapping technology unprecedentedly validated the successful activation of the SN38 prodrug and massive distribution throughout the solid tumors for thrombin-containing nanomedicine, in stark to apparent entrapment in tumor vasculature and stroma for the conventional thrombin-free nanomedicine. Hence, the multifunctionalities of our proposed dual prodrug nanomedicine is underscored by its ability to actively target cancerous cells, induce vasculature occlusion, and orchestrate a controlled release of chemotherapeutic agents.

Theranostic polymers have emerged as a versatile platform in cancer nanomedicine, integrating therapeutic and imaging functionalities to overcome challenges in oncology. Featuring diverse architectures such as linear polymers, dendrimers, star-like polymers, and bottle-brush polymers, these systems enable tumor-targeted drug delivery, real-time imaging, and controlled release. Recent advances in stimuli-responsive designs and biomimetic strategies have improved their specificity, stability, and adaptability, outperforming conventional nanocarriers. This review summarizes the design, synthesis, and biomedical applications of theranostic polymers, focusing on their potential to address tumor heterogeneity and biological barriers. The challenges of biocompatibility, immunogenicity, and clinical translation are discussed, with a perspective toward future developments in precision medicine and imaging-guided cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most feared diseases worldwide owing to its poor prognosis, negligible therapeutic advances, and high mortality. Herein, multifunctional enzyme-responsive micelles for the controlled delivery of paclitaxel (PTX) were prepared to circumvent its current clinical challenges. Accordingly, two enzyme-responsive structural units composed of Vitamin D3 (VD3) conjugated with polyethylene glycol of different molecular weights (600 Da and 2000 Da) were synthesized and characterized using different analytical methods. By applying the solvent evaporation method, these bioactive structural units self-assembled into sub-100 nm VD3 micelles with minimal batch-to-batch variation, monomodal particle size distribution, and high encapsulation efficiency. The enzyme-triggered disassembly of PTX-loaded VD3 micelles was demonstrated by release studies in the presence of a high esterase content typically featured by PDAC cells. PTX-loaded VD3 micelles also exhibited prominent cell internalization and induced a considerable cytotoxic synergistic effect against human PDAC cells (BxPC-3 cells) in 2D and 3D cell culture models compared with free PTX. The PTX-loaded VD3 micelles were hemocompatible and stable after long-term storage in the presence of biorelevant media, and showed higher efficiency to inhibit the tumor growth compared to the approved clinical nanoformulation (Abraxane®) in an in ovo tumor model. The findings reported here indicate that VD3S-PEG micelles may have a promising role in PDAC therapy, since VD3 could act not only as a hydrophobic core of the micelles but also as a therapeutic agent that provides synergetic therapeutic effects with the encapsulated PTX.

Pancreatic cancer is among the deadliest malignancies, with few treatment options for locally advanced, unresectable cases. Conventional therapies, such as chemoradiotherapy and hyperthermia, show promise but face challenges in improving outcomes. This study introduces a novel drug delivery system using gemcitabine (GEM)-loaded layer-by-layer magnetic nanoparticles (LBL MNPs) combined with alternating magnetic field (AMF) application and X-ray irradiation to enhance therapeutic efficacy. LBL MNPs were synthesized using optimized layering techniques to achieve superior drug loading and controlled release. Human pancreatic cancer cells (PANC-1) were treated with LBL MNPs alone, with AMF-induced hyperthermia, and in combination with X-rays. The results demonstrate that the 7-layer LBL MNPs exhibited optimal cytotoxicity, significantly reducing cell viability at concentrations of 30 µg/mL and higher. Combining 7-layer LBL MNPs with AMF increased cell death in a time- and concentration-dependent manner, achieving up to 98% inhibition of cell proliferation. The addition of X-rays to the regimen demonstrated a strong synergistic effect, resulting in a 13-fold increase in cell death compared to controls. These findings highlight the potential of this integrated approach to improve outcomes in patients with pancreatic cancer.

Computed tomography (CT) is widely used all over the world, and the detection rate of early lung adenocarcinoma is increasing. Minimally invasive thoracic surgery (MITS) has emerged as the preferred surgical approach for lung adenocarcinoma, but identifying small lung adenocarcinomas is difficult. Therefore, there is a need for a non-invasive, convenient and efficient way to localize lung adenocarcinomas.

A targeted gold nanocluster for intraoperative fluorescence imaging by intratracheal delivery has been designed. Au-GSH-anti Napsin A nanoclusters (NapA-AuNCs) were synthesized, and their physicochemical properties and optical properties were characterized. Target effect, cytotoxicity and fluorescence time curve of NapA-AuNCs, were tested in vivo and in vitro, and intratracheal delivery was also carried.

NapA-AuNCs targeting lung adenocarcinoma with red fluorescence and good mucus penetration were synthesized, which had the targeting property of A549 and lung adenocarcinoma tissue, and also had very low toxicity to normal lung epithelial cells and organs. Intracheal delivery involves faster imaging of lung adenocarcinoma and less accumulation of other organs than intravenous administration.

NapA-AuNCs targeting lung adenocarcinoma were successfully conjugated, and intratracheal delivery is a safe, effective for lung adenocarcinoma intraoperative localization.

Despite many advances in gene therapy, the delivery of small interfering RNAs is still challenging. Erythrocytes are the most abundant cells in the human body, and their membrane possesses unique features. From them, erythrocytes membrane vesicles can be generated, employable as nano drug delivery system with prolonged blood residence and high biocompatibility.

Human erythrocyte ghosts were extruded in the presence of siRNA, and the objects were termed EMVs (erythrocyte membrane vesicles). An ultracentrifugation-based method was applied to select only the densest EMVs, ie, those containing siRNA. We evaluated their activity in vitro in B16F10 cells expressing fluorescent tdTomato and in vivo in B16F10 tumor-bearing mice after a single injection.

The EMVs had a negative zeta potential, a particle size of 170 nm and excellent colloidal stability after one month of storage. With 0.3 nM siRNA, more than 75% gene knockdown was achieved in vitro, and 80% was achieved in vivo, at 2 days PI at 2.5 mg/kg. EMVs mostly accumulate around blood vessels in the lungs, brain and tumor. tdTomato fluorescence steadily decreased in tumor areas with higher EMVs concentration, which indicates efficient gene knockdown. Approximately 2% of the initial dose of EMVs was still present in the plasma after 2 days.

The entire production process of the purified siRNA-EMVs took approximately 4 hours. The erythrocyte marker CD47 offered protection against macrophage recognition in the spleen and in the blood. The excellent biocompatibility and pharmacokinetic properties of these materials make them promising platforms for future improvements, ie, active targeting and codelivery with conventional chemotherapeutics.

Given the unique capabilities of natural cell membranes, such as prolonged blood circulation and homotypic targeting, extensive research has been devoted to developing cell membrane-inspired nanocarriers for cancer therapy, while most focused on overcoming one or a few biological barriers. In fact, the journey of nanosystems from systemic circulation to tumor cells involves intricate processes, encompassing blood circulation, tissue accumulation, cancer cell targeting, endocytosis, endosomal escape, intracellular trafficking to target sites, and therapeutic action, all of which pose limitations to their clinical translation. This underscores the necessity of meticulously considering these biological barriers in the design of cell membrane-mimetic nanocarriers. In this review, we delineate the functions and applications of diverse types of cell membranes in nanocarrier systems. We elaborate on the biological hurdles encountered at each stage of the biomimetic nanoparticle's odyssey to the target, and comprehensively discuss the obstacles imposed by the tumor microenvironment for precise delivery. Subsequently, we systematically review contemporary cell membrane-based strategies aimed at overcoming these multi-level biological barriers, encompassing hybrid cell membrane (HCM) camouflage, tumor microenvironment remodeling, endosomal/lysosomal escape, multidrug resistance (MDR) reversal, optimization of nanoparticle physicochemical properties, and so on. Finally, we outline potential strategies to accelerate the development of cell membrane-inspired precision nanocarriers and discuss the challenges that must be addressed to enhance their clinical applicability. This review serves as a guide for refining the study of cell membrane-mimetic nanosystems in surmounting in vivo delivery barriers, thereby significantly contributing to advancing the development and application of cell membrane-based nanoparticles in cancer delivery.

In this study, we present the first comparative analysis of active and passive drug delivery systems for docetaxel (DTX) in prostate cancer using supramolecular self-assembled micellar nanovectors. Specifically, we developed two novel micelles based on polydiacetylenic amphiphiles (PDA) for passive and active targeting. The active targeting micelles were designed with a prostate-specific membrane antigen (PSMA) ligand, ACUPA, to facilitate recognition by PSMA-positive cancer cells. These PDA-based micelles feature a well-defined structure with a hydrophobic PDA core and a surface functionalized with PEG, and for active targeting, ACUPA. Our micelles demonstrated excellent encapsulation capacity, significantly improving DTX solubility in water, a crucial factor for clinical drug use. In vitro studies confirmed the safety and cytotoxic profiles of both systems, with ACUPA-functionalized micelles showing notable internalization into PSMA-positive LNCaP cells, mediated through the PSMA-ACUPA interaction. In vivo imaging revealed preferential accumulation of ACUPA-functionalized nanomicelles in LNCaP xenograft tumors, suggesting enhanced retention via specific ACUPA-PSMA interactions and active uptake by LNCaP cells. Notably, Balb/c-Foxn1nu/nu early in vivo studies showed a marked reduction in tumor volume and tumor expression levels of proliferation, cell cycle progression, cell survival and anti-apoptotic markers with DTX-loaded micelles functionalized with ACUPA compared to those without ACUPA. Overall, our studies collect initial evidence regarding the feasibility of supramolecular self-assembly of ACUPA-PDA-based nanomicelles for PSMA-targeted drug chemotherapy delivery developments.

Targeted protein degradation (TPD) strategies offer a significant advantage over traditional small molecule inhibitors by selectively degrading disease-causing proteins. While small molecules can lead to recurrence and resistance due to compensatory pathway activation, TPD addresses this limitation by promoting protein degradation, thereby reducing the likelihood of recurrence and resistance over the long-term. Despite these benefits, bifunctional TPD molecules face challenges such as low solubility, poor bioavailability, and limited tumor specificity. In this study, we developed polymer-based nanoparticles that combine TPD strategies with nanotechnology through a hydrophobic tagging method. Hydrophobic polymer-tagged nanoparticles facilitate targeted protein degradation by incorporating hydrophobic polymers that mimic hydrophobic residues in misfolded proteins. This system combines degradation and delivery capabilities within a polymer-based platform, inducing protein degradation while improving solubility, stability, and tumor targeting. These nanoparticles consist of a block copolymer composed of an androgen receptor ligand (ARL)-conjugated hydrophobic polylactic acid (PLA) and a hydrophilic polyethylene glycol (PEG), connected by a GSH-cleavable disulfide bond. In aqueous solutions, this block copolymer (ARL-PLA-SS-PEG) forms micelles that degrade in reducible cellular environments. The micelles demonstrated significant in vitro degradation of the target androgen receptor (AR). Furthermore, they achieved substantial tumor accumulation and significantly inhibited tumor growth in a tumor-bearing mouse model. A mechanistic study revealed that the micelle-mediated TPD follows a dual pathway involving both proteasome and autophagosome. This approach has the potential to serve as a universal platform for protein degradation, eliminating the need to develop disease-specific TPD molecules.

Recently, cancer therapy has witnessed remarkable advancements with a growing focus on precision medicine and targeted drug delivery strategies. The application of anionic polysaccharides has gained traction in various drug delivery systems. Anionic polysaccharides have emerged as promising delivery carriers in cancer therapy and theranostics, offering numerous advantages such as biocompatibility, low toxicity, and the ability to encapsulate and deliver therapeutic agents to tumor sites with high specificity. This review underscores the significance of anionic polysaccharides as essential components of the evolving landscape of cancer therapy and theranostics. These polymers can be tailored to carry a wide range of therapeutic cargo, including chemotherapeutic agents, nucleic acids, and imaging agents. Their negative charge enables electrostatic interactions with positively charged drugs and facilitates the formation of stable nanoparticles, liposomes, or hydrogels for controlled drug release. Additionally, their hydrophilic nature aids in prolonging circulation time, reducing drug degradation, and minimizing off-target effects. Besides, some of them could act as targeting agents or therapeutic compounds that lead to improved therapeutic performance. This review offers valuable information for researchers, clinicians, and biomedical engineers. It provides insights into the recent progress in the applications of anionic polysaccharide-based delivery platforms in cancer theranostics to transform patient outcomes.

Accurately predicting nanomedicine accumulation is critical for guiding patient stratification and optimizing treatment strategies in the context of precision medicine. However, non-invasive prediction of nanomedicine accumulation remains challenging, primarily due to the complexity of identifying relevant imaging features that predict accumulation. Here, a novel non-invasive method is proposed that utilizes standard-of-care medical imaging modalities, including computed tomography and ultrasound, combined with a radiomics-based model to predict nanomedicine accumulation in tumor. The model is validated using a test dataset consisting of seven tumor xenografts in mice and three sizes of gold nanoparticles, achieving an area under the receiver operating characteristic curve of 0.851. The median accumulation levels of tumors predicted as "high accumulators" are 2.69 times greater than those predicted as "low accumulators". Analysis of this machine-learning-driven interpretable radiomics model revealed imaging features that are strongly correlated with dense stroma, a recognized biological barrier to effective nanomedicine delivery. Radiomics-based prediction of tumor accumulation holds promise for stratifying patient and enabling precise tailoring of nanomedicine treatment strategies.

Poor tumor penetration is the major predicament of nanomedicines that limits their anticancer efficacy. The dense extracellular matrix (ECM) in the tumor is one of the major barriers against the deep penetration of nanomedicines. In this work, a slimming/excavating strategy is proposed for enhanced intratumoral penetration based on an acid-disassemblable nanomicelles-assembled nanomedicine and the NO-mediated degradation of ECM. The nanomedicine is constructed by cross-linking nanomicelles, which are self-assembled with two kinds of dendrimers containing phenylboronic acid and lactobionic acid, through borate esterification. In the acidic tumor microenvironment, the pH-sensitive borate ester bonds among the nanomicelles are hydrolyzed, triggering the disassembly of nanomedicine (≈150 nm) into small nanomicelles (≈25 nm). In response to the intratumoral over-expressed glutathione (GSH), the NO donor loaded in the nanomicelles produces NO, which mediates the expression of matrix metalloproteinases for the degradation of ECM in the tumor. By collaboration of the disassembling behavior of nanomedicine with the NO-mediated degradation of ECM, the designed nanomedicine can penetrate a long distance in tumors. The proposed slimming/excavating strategy will provide inspiration for overcoming the challenge of nanomedicines in tumor penetration.

The existing study focuses on the development, optimization, and evaluation of sorafenib-loaded polymeric nanomicelles for posterior segment delivery in treating retinoblastoma. The formulation involved adjusting various process and product parameters to create effective drug-loaded polymeric nanomicelles. The particle size, PDI, and zeta potential of optimized formulation were found to be 65.52 ± 1.18 nm, 0.14 ± 0.01, and -3.26 ± 0.66 mV, respectively. The entrapment efficiency and drug release were estimated to be 98.84% ± 0.001 and 99.99% in 6 h, respectively. Additionally, the optimized formulation demonstrated acceptable outcomes for solid-state analysis, osmolality, pH, residual solvent, and morphological properties. After 8 h, the ex vivo transcleral permeation and scleral deposition were 629.05 ± 124.11 ng/cm2 and 4.10 ± 0.54 µg, respectively. Y-79 (human retinoblastoma) cell line study using standard drug, test drug, and optimized formulation revealed anticancer potential at all time points (6, 12, 18, and 24 h) with comparable IC50 values. Furthermore, the optimized formulation exhibited no toxicity on the ARPE-19 (human retinal pigmented epithelium) cell line over 24 h. The optimized formulation was non-irritating to the eye (HET-CAM) and remained stable for 6 months. Thus, drug delivery to the posterior eye segment for the treatment of retinoblastoma appears to be possible with the help of established technology.

Plant-derived nanovesicles (PDNVs), including plant extracellular vesicles (EVs) and plant exosome-like nanovesicles (ELNs), are natural nano-sized membranous vesicles containing bioactive molecules. PDNVs consist of a bilayer of lipids that can effectively encapsulate hydrophilic and lipophilic drugs, improving drug stability and solubility as well as providing increased bioavailability, reduced systemic toxicity, and enhanced target accumulation. Bioengineering strategies can also be exploited to modify the PDNVs to achieve precise targeting, controlled drug release, and massive production. Meanwhile, they are capable of crossing the blood-brain barrier (BBB) to transport the cargo to the lesion sites without harboring human pathogens, making them excellent therapeutic agents and drug delivery nanoplatform candidates for brain diseases. Herein, this article provides an initial exposition on the fundamental characteristics of PDNVs, including biogenesis, uptake process, isolation, purification, characterization methods, and source. Additionally, it sheds light on the investigation of PDNVs' utilization in brain diseases while also presenting novel perspectives on the obstacles and clinical advancements associated with PDNVs.

Conventional cancer therapies such as chemotherapy face challenges such as poor tumor targeting, systemic toxicity, and drug resistance. Nanotechnology offers solutions through advanced drug delivery systems that preferentially accumulate in tumors while avoiding healthy tissues. Recent innovations have enabled the optimization of engineered nanocarriers for extended circulation and tumor localization via both passive and active targeting mechanisms. Passive accumulation exploits the leaky vasculature of tumors, whereas active strategies use ligands to selectively bind cancer cell receptors. Multifunctional nanoparticles also allow the combination of imaging, multiple therapeutic modalities and on-demand drug release within a single platform. Overall, precisely tailored nanotherapeutics that leverage unique pathophysiological traits of malignancies provide opportunities to overcome the limitations of traditional treatment regimens. This emerging field promises more effective and personalized nanomedicine approaches to detect and treat cancer. The key aspects highlighted in this review include the biological barriers associated with nanoparticles, rational design principles to optimize nanocarrier pharmacokinetics and tumor uptake, passive and active targeting strategies, multifunctionality, and reversal of multidrug resistance.

A biodegradable and biocompatible micellar-based drug delivery system was developed using amphiphilic methoxy-poly(ethylene glycol)-cholesterol (C1) and poly(ethylene glycol)-S-S-cholesterol (C2) conjugates and applied to the tumoral release of the water-insoluble drug curcumin. These synthesized surfactants C1 and C2 were found to form stable micelles (CMC ∼ 6 μM) and an average hydrodynamic size of around 20-25 nm. The curcumin-encapsulated C1 micelle was formulated by a solvent evaporation method. A very high drug encapsulation efficiency (EE) of ∼88% and a drug loading (DL) capacity of ∼9% were determined for both the micelles. From the reduced rate of curcumin degradation and differential scanning calorimetry (DSC) analysis, the stability of the curcumin-loaded C1 micelle was found to be higher than that of the unloaded micelle, which confirmed a more compact structural arrangement in the presence of hydrophobic curcumin. A pH-sensitive release of curcumin (faster release with decrease in pH) was observed for the curcumin-loaded C1 micelle, attributed to the diffusion and relaxation/erosion of micellar aggregates. To achieve reduction environment-sensitive drug release, a disulfide (S-S) chemical linkage-incorporated mPEG-cholesterol conjugate (C2) was synthesized, which was found to show glutathione-responsive faster release of curcumin. The in vitro experiments carried out in SCC9 oral cancer cell lines showed that the blank C1 and C2 micelles were noncytotoxic at lower concentrations (<50 μM), while curcumin-loaded C1 and C2 micelles inhibited the proliferation and promoted the apoptosis. An increased in vitro cytotoxicity was observed for curcumin-loaded micelles compared to that of curcumin itself, demonstrating a better cell penetration efficacy of the micelle. These results were further supplemented by the in vivo anticancer analysis of the curcumin-loaded C1 and C2 micellar formulations using the mice xenograft model. Notably, curcumin-loaded C2 micelles showed a significantly stronger apoptotic effect in xenograft mice compared to curcumin-loaded C1 micelles, indicating the GSH environment-sensitive drug release and improved bioavailability. In conclusion, the mPEG-cholesterol C1 and C2 micellar system with the advantages of small size, high encapsulation efficiency, high drug loading, simple preparing technique, biocompatibility, and good in vitro and in vivo performance may have the potential to be used as a drug carrier for sustained and stimuli-responsive release of the hydrophobic drug curcumin.

Unlike homogeneous liposomes, phase-separated liposomes have the potential to be attractive soft materials because they exhibit different properties for each phase. In this study, phase separation was observed when liposomes were prepared using 1,2-dioleoyloxy-3-trimethylammonium propane chloride (DOTAP), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and cholesterol. The pH of the DOTAP-rich phase was evaluated using a coumarin derivative, and measurements showed that DOTAP molecules accumulated hydroxyl ions (OH-) in the DOTAP-rich phase. Such accumulation of OH- was not observed when homogeneous DSPC liposomes were used. The difference in local concentration of OH- in each phase was applied to prepare hollow silica particles with large pores. The OH- promotes the polymerization of tetraethyl orthosilicate (TEOS). Therefore, TEOS polymerized preferentially in the DOTAP-rich phase, whereas a silica membrane barely formed in the DSPC-rich phase.

The size of nanodrugs plays a crucial role in shaping their chemical and physical characteristics, consequently influencing their therapeutic and diagnostic interactions within biological systems. The optimal size of nanomedicines, whether small or large, offers distinct advantages in disease treatment, creating a dilemma in the selection process. Addressing this challenge, size-transformable nanodrugs have surfaced as a promising solution, as they can be tailored to entail the benefits associated with both small and large nanoparticles. In this review, various strategies are summarized for constructing size-transformable nanosystems with a focus on nanotherapeutic applications in the field of biomedicine. Particularly we highlight recent research developments in cancer therapy. This review aims to inspire researchers to further develop various toolboxes for fabricating size-transformable nanomedicines for improved intervention against diverse human diseases.

In this study, DOX (Doxorubicin) and Fe3O4 magnetic nanocrystals (SPIONs (Superparamagnetic iron oxide nanocrystals)) were encapsulated in the PLGA-PEG: poly(lactide-co-glycolide)-b-poly(ethylene glycol) nanoparticles for theranostic purposes. The final prepared formulation which is called NPs (Nanoparticles) exhibited a particle size with a mean diameter of ~ 209 nm and a sufficient saturation magnetization value of 1.65 emu/g. The NPs showed faster DOX release at pH 5.5 compared to pH 7.4. Also, the cytotoxicity effect of NPs increased compared to Free-DOX alone in C6 glioma cancer cells. For in vivo investigations, the 2.2 Kg rabbits were injected with NPs formulations via a central articular anterior vein in their ears. Furthermore, the images of rabbit organs were depicted via MR (Magnetic resonance) and fluorescent imaging techniques. A negative contrast (dark signal) was observed in T2 (Relaxation Time) weighted MR images of IV (Intravenously)-injected rabbits with NPs compared to the control ones. The organ's florescent images of NPs-injected rabbits showed a high density of red color related to the accumulation of DOX in liver and kidney organs. These data showed that the NPs have no cytotoxicity effect on the heart. Also, the results of histopathological tests of different organs showed that the groups receiving NPs and Free-DOX were almost similar and no significant difference was seen, except for the cardiac tissue in which the pathological effects of NPs were significantly less than the Free-DOX. Additionally, pharmacokinetic studies were also conducted at the sera and whole bloods of IV-injected rabbits with NPs and Free-DOX. The pharmacokinetic parameters showed that NPs could enhance the DOX retention in the serum compared to the Free-DOX. Altogether, we aimed to produce a powerful delivery nanosystem for its potential in dual therapeutic and diagnostic applications which are called theranostic agents.

The complex and heterogeneous nature of cancer necessitates the development of innovative multifunctional nanomedicines (MN). Hyaluronic acid (HA) is a functional carbohydrate polysaccharide that is widely used in various biomedical fields. In this study, we employed HA as a stabilizer and regulator for the synthesis of a size-tunable nanomedicine comprising ferric ions, doxorubicin, and epigallocatechin gallate (EGCG), referred to as HDE-MN, for cancer therapy. A change in the HA ratio can yield HDE-MNs with sizes varying from ~20 nm to over 100 nm. Modified HA can respond to hyaluronidase (HAase) to provide controllable pH/HAase dual-responsive drug release for improved cancer therapy. Moreover, HA can mediate the targeted delivery of HDE-MNs both in vitro and in vivo to cancer cells. In addition, HDE-MNs reversed multidrug resistance owing to the incorporation of EGCG, inducing ferroptosis due to the involvement of ferric ions. More importantly, HDE-MNs have a photothermal conversion effect, enabling photothermal therapy, photothermally enhanced drug release, and ferroptosis, which collectively contribute to significantly improved cancer therapy. Therefore, the HDE-MNs with laser irradiation achieved full ablation of the in vivo tumors. Together with its good biocompatibility, HDE-MNs may be promising for effective cancer therapy.

Sensory neurons within the dorsal root ganglion (DRG) are the primary trigger of pain, relaying activity about noxious stimuli from the periphery to the central nervous system; however, targeting DRG neurons for pain management has remained a clinical challenge. Here, we demonstrate the use of lipid nanoparticles (LNPs) for effective intrathecal delivery of small interfering RNA (siRNA) to DRG neurons, achieving potent silencing of the transient receptor potential vanilloid 1 (TRPV1) ion channel that is predominantly expressed in nociceptor sensory neurons. This leads to a reversible interruption of heat-, capsaicin-, and inflammation-induced nociceptive conduction, as observed by behavioral outputs. Our work provides a proof-of-concept for intrathecal siRNA therapy as a novel and selective analgesic modality.

Background/Objectives: Radiotherapy is a widely applied first-line clinical treatment modality of cancer. Copper-cysteamine (Cu-Cy) nanoparticles represent a new type of photosensitizer that demonstrates significant anti-tumor potential by X-ray-induced photodynamic therapy. Iodide is a high-Z element with superior X-ray absorption ability and has the β-decay radiotherapeutic nuclide, 131I, which emits Cherenkov light. In this study we aimed to investigate the X-ray-induced photodynamic therapy potential of iodinated Cu-Cy (Cu-Cy-I) nanoparticles and also explore the local treatment efficacy of 131I-labeled Cu-Cy-I ([131I]Cu-Cy-I) nanoparticles. Methods: The synthesis of [131I]Cu-Cy-I nanoparticles was performed with [131I]I- anions. The in vitro radiobiological effects on tumor cells incubated with Cu-Cy-I nanoparticles by X-ray irradiation were investigated. The in vivo tumor growth-inhibitory effects of the combination of Cu-Cy-I nanoparticles with X-ray radiotherapy and [131I]Cu-Cy-I nanoparticles were evaluated with 4T1 tumor-xenografted mice. Results: The in vitro experiment results indicated that the X-ray irradiation with the presence of Cu-Cy-I nanoparticles produced a higher intracellular reactive oxygen species (ROS) level and more DNA damage of 4T1 cells and showed a stronger tumor cell killing ability compared to X-ray irradiation alone. The in vivo experimental results with 4T1 breast carcinoma-bearing mice showed that the combination of an intratumoral injection of Cu-Cy-I nanoparticles and X-ray radiotherapy enhanced the tumor growth-inhibitory effect and prolonged the mice's lives. Conclusions: Cu-Cy-I nanoparticles have good potential as new radiosensitizers to enhance the efficacy of external X-ray radiotherapy. However, the efficacy of local treatment with [131I]Cu-Cy-I nanoparticles at a low 131I dose was not verified. The effective synthesis of smaller sizes of nanoparticles is necessary for further investigation of the radiotherapy potential of [131I]Cu-Cy-I nanoparticles.

Bacterial outer membrane vesicles (OMVs) have emerged as promising vehicles for anticancer drug delivery due to their inherent tumor tropism, immune-stimulatory properties, and potential for functionalization with therapeutic proteins. Despite their advantages, the high lipopolysaccharide (LPS) endotoxin content in the OMVs raises significant safety and regulatory challenges. In this work, we produce LPS-attenuated and LPS-free OMVs and systematically assess the effects of LPS modification on OMVs' physicochemical characteristics, membrane protein content, immune-stimulatory capacity, tolerability, and anticancer efficacy. Our findings reveal that LPS removal increased the maximal tolerated dose of the OMVs by over 25-fold. When adjusted for comparable safety profiles, LPS-free OMVs exhibit superior anticancer effects compared with wild-type OMVs. Mechanistic investigations indicate that the LPS removal obviates immune cell death caused by LPS and reduces the negatory effects of wild type of OMVs on tumor immune cell infiltrates. We further show the functionality of the LPS-free OMV through the incorporation of an IL-2 variant protein (Neo-2/15). This functionalization augments OMV's ability of the OMV to inhibit tumor growth and promote lymphocyte infiltration into the tumor microenvironment. This study presents a safe and functionalizable OMV with improved translational prospect.

The YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two important transcriptional coactivators that are often aberrantly activated in cancer cells. Their dysregulation promotes cancer development and can confer resistance to anticancer therapies. Therefore, the pharmacological inhibition of YAP/TAZ presents a promising approach for treating tumors with heightened YAP/TAZ activity. However, the clinical use of a known YAP/TAZ inhibitor, niflumic acid (NA), is limited by its poor in vivo half-life. To improve its bioavailability, we developed a series of NA-based prodrug polymers and investigated the impact of NA monomer units on the physicochemical properties of their self-assembled nanoparticles. The optimal pNA polymer was selected as a prodrug micellar nanocarrier to load hydrophobic receptor tyrosine kinase inhibitors (RTKIs) for combination therapy. The nanocarrier selectively accumulated in the tumor and synergistically inhibited tumor growth with the cargo RTKIs, particularly Dasatinib, introducing a nanocombination therapy enhanced breast cancer treatment.

Since the discovery of d-amino acids, they have been considered inactive and have not been used as potent drugs. Here, we report that simple mixing with poly(vinyl alcohol) (PVA) unleashed latent potentials of d-amino acids in boron neutron capture therapy (BNCT). PVA formed boronate esters with seemingly useless boronated d-amino acids and induced tumor-associated amino acid transporter-superselective internalization and prolonged intracellular retention, accomplishing complete cure of tumors. The superselective internalization was achieved by switching the internalization pathway from ineffective pass through the transporter to the transporter-mediated endocytosis. The acidic environment in the endo-/lysosome dissociated the boronate esters and elicited the stealthiness of the drugs, preventing their externalization and prolonging intracellular retention time. In a subcutaneous tumor model, this system accomplished surprisingly high tumor-selective accumulation that could not be achieved by conventional approaches and induced drastic BNCT effects. PVA may be a unique material to unlock potentials of seemingly inert molecules.

The immunosuppressive tumor microenvironment and limited intratumoral permeation have largely constrained the outcome of tumor therapy. Herein, we report a tailored DNA structure-based nanoplatform with striking tumor-penetrating capability for targeted remodeling of the immunosuppressive tumor microenvironment in vivo. In our design, chemo-immunomodulator (gemcitabine) can be precisely grafted on DNA sequences through a reactive oxygen species (ROS)-sensitive linker. After self-assembly, the gemcitabine-grafted DNA structure can site-specifically organize legumain-activatable melittin pro-peptide (promelittin) on each vertex for intratumoral delivery and further function as the template to load photosensitizers (methylene blue) for ROS production. The tailored DNA nanoplatform can achieve targeted accumulation, highly improved intratumoral permeation, and efficient immunogenic cell death of tumor cells by laser irradiation. Finally, the immunosuppressive tumor microenvironment can be successfully remodeled by reducing multi-type immunosuppressive cells and enhancing the infiltration of cytotoxic lymphocytes in the tumor. This rationally developed multifunctional DNA nanoplatform provides a new avenue for the development of tumor therapy.