Supramolecular materials represent a powerful class of platforms in cancer diagnosis and therapy, owing to their dynamic architectures, stimuli responsiveness, and high biocompatibility. This review focused on three representative categories-Pillarene-based systems, virus-mimetic nanoparticles (VMNs), and metal-organic frameworks (MOFs)-each offering unique structural and functional properties. Pillarene-based assemblies enable precise host-guest interactions, by being classified into amphiphilic, ionic, and chiral varieties, the robust drug loading and controlled release capabilities of the Pillarene family were emphasized. At the same time, the VMNs, including virus-like particles and virosomes, show power in cancer cell targeting and membrane penetration by emulating natural viral architectures. By discussing the fabrication and application of single-metallic, multi-metallic, and composite MOFs, their potential in multimodal diagnosis and therapy was revealed. In addition, other supramolecular categories, such as cyclodextrin and dendrimers, were introduced as well. We highlighted representative approaches and emerging methods, and comparative perspectives with traditional nanocarriers were included. A critical evaluation of pharmacokinetic behaviors, biosafety concerns, and translational limitations was also proposed, aiming to guide future research in supramolecular cancer nanomedicine. Through an integrative and forward-looking analysis, this review provided a comprehensive framework for understanding and designing supramolecular systems for precision oncology. These emerging nanotechnologies hold promise to reshape cancer medicine by enabling adaptive, targeted, and multifunctional therapeutic strategies.

Integrating photodynamic therapy (PDT) and chemodynamic therapy (CDT) shows promising potential in tumor treatment. Nevertheless, the lack of specific tumor targeting, serious photobleaching, and poor photothermal effect of photosensitizers, the intracellular low Fenton reaction efficiency, and glutathione (GSH)-elicited reactive oxygen species (ROS) depletion profoundly restrict ROS-mediated cancer therapy. To enhance ROS generation with the assistance of photothermal therapy (PTT), the hyaluronic acid (HA)-decorated Fe-MIL-88B (MIL) nanocatalysts were fabricated for tumor-targeted delivery of photosensitizer IR820. The IR820@HA-coated MIL (IHM) nanocatalysts remarkably enhanced the photothermal conversion efficacy and singlet oxygen (1O2) production of IR820 and lowered IR820 photobleaching. The IHM nanocatalysts promoted the conversion of H2O2 into toxic ·OH upon thermo/acidity-enhanced Fe3+-mediated Fenton reaction and consumed GSH via Fe3+-elicited GSH oxidation. After being internalized by 4 T1 cancer cells via CD44-mediated endocytosis, the IHM nanocatalysts under irradiation of near-infrared (NIR) laser prominently produced hyperthermia and strong ROS storm, thereby causing apoptosis and ferroptosis via mitochondria damage and lipid peroxidation, and inducing immunogenic cell death (ICD). Through HA-mediated tumor targeting, the IHM nanocatalysts effectively accumulated in 4 T1 tumor and inhibited tumor growth and lung metastasis by PTT-enhanced PDT/CDT combined with ferroptosis and ICD-amplified antitumor immune response, showing great promise in future tumor treatment.

Triple-negative breast cancer (TNBC) is recognized as a particularly aggressive subtype of breast cancer that is devoid of effective therapeutic targets. Immune checkpoint inhibitors (ICIs) have demonstrated promising results in TNBC treatment. Nonetheless, most patients either develop resistance to ICIs or fail to respond to them initially. Owing to its spatio-temporal precision and non-invasive nature, photoimmunotherapy offers a targeted therapeutic strategy for TNBC. Herein, we report hyaluronic acid (HA)-functionalized indocyanine green-based supramolecular nanoparticles (HGI NPs), with biodegradable characteristics, for high-performance photoacoustic imaging and targeted phototherapy for TNBC. Notably, HGI NPs can significantly gather in TNBC tissues because of the enhanced permeability and retention effect of the tumor, and the tumor-targeting properties of HA. The strong amplification of HGI nanoparticles triggers a significant immunogenic cell death (ICD) response when exposed to 808 nm light, thus shifting the immunosuppressive tumor microenvironment (iTME) into a tumor attack mode and 'hot' state. Antitumor experiments demonstrate the high efficiency of the supramolecular photosensitizers HGI NPs for TNBC elimination and good biosafety. This synergistic strategy reshapes the iTME and amplifies the antitumor immune response, providing a theoretical foundation for combining phototherapy and ICIs as potential treatments for TNBC.

Chemo-immunotherapy based on inducing tumor immunogenic cell death (ICD)with chemotherapy drugs has filled the gaps between traditional chemotherapy and immunotherapy. It is verified that paclitaxel (PTX) can induce breast tumor ICD. From this basis, a kind of nanoparticle that can efficiently deliver different drug components simultaneously is constructed. The purpose of this study is for the sake of exploring the scheme of chemotherapy-induced ICD combined with other immunotherapy to enhance tumor immunogenicity and inhibit the growth, metastasis, and recurrence of breast tumors, so as to provide a research basis for solving the tough problem of breast cancer treatment.

Nanomedicine loaded with PTX, small interference RNA that suppresses CD47 expression (CD47siRNA, siCD47), and immunomodulator R848 were prepared by the double emulsification method. The hydrodynamic diameter and zeta potential of NP/PTX/siCD47/R848 were characterized. Established the tumor-bearing mice model of mouse breast cancer cell line (4T1) in situ and observed the effect of intravenous injection of NP/PTX/siCD47/R848 on the growth of 4T1 tumor in situ. Flow cytometry was used to detect the effect of drugs on tumor immune cells.

NP/PTX/siCD47/R848 nano-drug with tumor therapeutic potential were successfully prepared by double emulsification method, with particle size of 121.5 ± 4.5 nm and surface potential of 36.1 ± 2.5 mV. The calreticulin on the surface of cell membrane and extracellular ATP or HMGB1 of 4T1 cells increased through treatment with NPs. NP/PTX-treated tumor cells could cause activation of BMDCs and BMDMs. After intravenous injection, NP/PTX could quickly reach the tumor site and accumulate for 24 h. The weight and volume of tumor in situ in the breast cancer model mice injected with nanomedicine through the tail vein were significantly lower than those in the PBS group. The ratio of CD8+/CD4+ T cells in the tumor microenvironment and the percentage of dendritic cells in peripheral blood increased significantly in breast cancer model mice injected with nano-drugs through the tail vein.

Briefly, the chemotherapeutic drug paclitaxel can induce breast cancer to induce ICD. The nanomedicine which can deliver PTX, CD47siRNA, and R848 at the same time was prepared by double emulsification. NP/PTX/siCD47/R848 nano-drug can be enriched in the tumor site. The experiment of 4T1 cell tumor-bearing mice shows that the nano-drug can enhance tumor immunogenicity and inhibit breast tumor growth, which provides a new scheme for breast cancer treatment. (Graphical abstract).

Due to the heterogeneity of the tumor microenvironment, the clinical efficacy of tumor treatment is not satisfied, highlighting the necessity for new strategies to tackle this issue. To effectively treat breast tumors by tumor-targeted chemo/chemodynamic therapy, herein, the Fe3+-rich MIL-88B nanobullets (MNs) covered with hyaluronic acid (HA) were fabricated as vehicles of zoledronic acid (ZA). The attained ZA@HMNs showed a high ZA payload (ca 29.6 %), outstanding colloidal stability in the serum-containing milieu, and accelerated ZA as well as Fe3+ release under weakly acidic and glutathione (GSH)-rich conditions. Also, the ZA@HMNs consumed GSH by GSH-mediated Fe3+ reduction and converted H2O2 into OH via Fenton or Fenton-like reaction with pH reduction. After being internalized by 4T1 cells upon CD44-mediated endocytosis, the ZA@HMNs depleted intracellular GSH and degraded H2O2 into OH, thus eliciting lipid peroxidation and mitochondria damage to suppress cell proliferation. Also, the ZA@HMNs remarkably killed macrophage-like RAW 264.7 cells. Importantly, the in vivo studies and ki67 and GPX4 staining of tumor sections demonstrated that the ZA@HMNs efficiently accumulated in 4T1 tumors to hinder tumor growth via ZA chemotherapy combined with OH-mediated ferroptosis. This work presents a practicable strategy to fabricate ZA@HMNs for breast tumor-targeted chemo/chemodynamic therapy with potential clinical translation.

Recently, metal-organic frameworks (MOFs) have attracted much attention as versatile materials for drug delivery and personalized medicine. MOFs are porous structures made up of metal ions coupled with organic ligands. This review highlights the synthesis techniques used to design MOFs with specific features such as surface area and pore size, and the drug encapsulation within MOFs not only improves their stability and solubility but also allows for controlled release kinetics, which improves therapeutic efficacy and minimizes adverse effects. Furthermore, it discusses the challenges and potential advantages of MOF-based drug delivery, such as MOF stability, biocompatibility, and scale-up production. With further advancements in MOF synthesis, functionalization techniques, and understanding of their interactions using biological systems, MOFs can have significant promise for expanding the area of personalized medicine and improving patient outcomes.

The field of oncology has transformed in recent years, with treatments shifting from traditional surgical resection and radiation therapy to more diverse and customized approaches, one of which is immunotherapy. ICD (immunogenic cell death) belongs to a class of regulatory cell death modalities that reactivate the immune response by facilitating the interaction between apoptotic cells and immune cells and releasing specific signaling molecules, and DAMPs (damage-associated molecular patterns). The inducers of ICD can elevate the expression of specific proteins to optimize the TME (tumor microenvironment). The use of nanotechnology has shown its unique potential. Nanomaterials, due to their tunability, targeting, and biocompatibility, have become powerful tools for drug delivery, immunomodulators, etc., and have shown significant efficacy in clinical trials. In particular, these nanomaterials can effectively activate the ICD, trigger a potent anti-tumor immune response, and maintain long-term tumor suppression. Different types of nanomaterials, such as biological cell membrane-modified nanoparticles, self-assembled nanostructures, metallic nanoparticles, mesoporous materials, and hydrogels, play their respective roles in ICD induction due to their unique structures and mechanisms of action. Therefore, this review will explore the latest advances in the application of these common nanomaterials in tumor ICD induction and discuss how they can provide new strategies and tools for cancer therapy. By gaining a deeper understanding of the mechanism of action of these nanomaterials, researchers can develop more precise and effective therapeutic approaches to improve the prognosis and quality of life of cancer patients. Moreover, these strategies hold the promise to overcome resistance to conventional therapies, minimize side effects, and lead to more personalized treatment regimens, ultimately benefiting cancer treatment.

Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Nanoscale metal-organic frameworks (MOFs) offer high biocompatibility, nanomaterial permeability, substantial specific surface area, and well-defined pores. These properties make MOFs valuable in biomedical applications, including biological targeting and drug delivery. They also play a critical role in tumor diagnosis and treatment, including tumor cell targeting, identification, imaging, and therapeutic methods such as drug delivery, photothermal effects, photodynamic therapy, and immunogenic cell death. The diversity of MOFs with different metal centers, organics, and surface modifications underscores their multifaceted contributions to tumor research and treatment. This review is a summary of these roles and mechanisms. The final section of this review summarizes the current state of the field and discusses prospects that may bring MOFs closer to pharmaceutical applications.

The applications of nanoreactors in biology are becoming increasingly significant and prominent. Specifically, nanoreactors with spatially confined, due to their exquisite design that effectively limits the spatial range of biomolecules, attracted widespread attention. The main advantage of this structure is designed to improve reaction selectivity and efficiency by accumulating reactants and catalysts within the chambers, thus increasing the frequency of collisions between reactants. Herein, the recent progress in the synthesis of spatially confined nanoreactors and their biological applications is summarized, covering various kinds of nanoreactors, including porous inorganic materials, porous crystalline materials with organic components and self-assembled polymers to construct nanoreactors. These design principles underscore how precise reaction control could be achieved by adjusting the structure and composition of the nanoreactors to create spatial confined. Furthermore, various applications of spatially confined nanoreactors are demonstrated in the biological fields, such as biocatalysis, molecular detection, drug delivery, and cancer therapy. These applications showcase the potential prospects of spatially confined nanoreactors, offering robust guidance for future research and innovation.

Immunotherapy has emerged as a promising cancer treatment option in recent years. In immune "hot" tumors, characterized by abundant immune cell infiltration, immunotherapy can improve patients' prognosis by activating the function of immune cells. By contrast, immune "cold" tumors are often less sensitive to immunotherapy owing to low immunogenicity of tumor cells, an immune inhibitory tumor microenvironment, and a series of immune-escape mechanisms. Immunogenic cell death (ICD) is a promising cellular process to facilitate the transformation of immune "cold" tumors to immune "hot" tumors by eliciting innate and adaptive immune responses through the release of (or exposure to) damage-related molecular patterns. Accumulating evidence suggests that various traditional therapies can induce ICD, including chemotherapy, targeted therapy, radiotherapy, and photodynamic therapy. In this review, we summarize the biological mechanisms and hallmarks of ICD and introduce some newly discovered and technologically innovative inducers that activate the immune system at the molecular level. Furthermore, we also discuss the clinical applications of combing ICD inducers with cancer immunotherapy. This review will provide valuable insights into the future development of ICD-related combination therapeutics and potential management for "cold" tumors.

Immunogenic cell death (ICD) is a special pattern of tumor cell death, enabling to elicit tumor-specific immune response via the release of damage-associated molecular patterns and tumor-associated antigens in the tumor microenvironment. ICD-induced immunotherapy holds the promise for completely eliminating tumors and long-term protective antitumor immune response. Increasing ICD inducers have been discovered for boosting antitumor immunity via evoking ICD. Nonetheless, the utilization of ICD inducers remains insufficient owing to serious toxic reactions, low localization efficiency within the tumor microenvironmental niche, etc. For overcoming such limitations, stimuli-responsive multifunctional nanoparticles or nanocomposites with ICD inducers have been developed for improving immunotherapeutic efficiency via lowering toxicity, which represent a prospective scheme for fostering the utilization of ICD inducers in immunotherapy. This review outlines the advances in near-infrared (NIR)-, pH-, redox-, pH- and redox-, or NIR- and tumor microenvironment-responsive nanodelivery systems for ICD induction. Furthermore, we discuss their clinical translational potential. The progress of stimuli-responsive nanoparticles in clinical settings depends upon the development of biologically safer drugs tailored to patient needs. Moreover, an in-depth comprehending of ICD biomarkers, immunosuppressive microenvironment, and ICD inducers may accelerate the advance in smarter multifunctional nanodelivery systems to further amplify ICD.

Recent preclinical and clinical studies have demonstrated that for cancer treatment, combination therapies are more effective than monotherapies in reducing drug-related toxicity, decreasing drug resistance, and improving therapeutic efficacy. With the rapid development of nanotechnology, the combination of metal-organic frameworks (MOFs) and multi-mode therapy offers a realistic possibility to further improve the shortcomings of cancer treatment. This article focuses on the latest developments, achievements, and treatment strategies of representative multifunctional MOF combination therapies for cancer treatment in recent years, which include not only bimodal combination therapies, but also multi-modal synergistic therapies, further demonstrating the effectiveness and superiority of the MOF drug delivery systems in cancer treatment.

The therapeutic effectiveness of the most widely used anticancer drug 5-fluorouracil (5-FU) is constrained by its high metabolism, short half-life, and rapid drug resistance after chemotherapy. Although various nanodrug delivery systems have been reported for skin cancer therapy, their retention, penetration and targeting are still a matter of concern. Hence, in the current study, a topical gel formulation that contains a metal-organic framework (zeolitic imidazole framework; ZIF-8) loaded with 5-FU and a surface modified with sonidegib (SDG; acting as a therapeutic agent as well as a targeting ligand) (5-FU@ZIF-8 MOFs) is developed against DMBA-UV-induced BCC skin cancer in rats. The MOFs were prepared using one-pot synthesis followed by post drug loading and SDG conjugation. The optimized MOFs were incorporated into hyaluronic acid-hydroxypropyl methyl cellulose gel and further subjected to characterization. Enhanced skin deposition of the 5-FU@ZIF-8-SDG MOFs was observed using ex vivo skin permeation studies. Confocal laser microscopy studies showed that 5-FU@ZIF-8-SDG MOFs permeated the skin via the transfollicular pathway. The 5-FU@ZIF-8-SDG MOFs showed stronger cell growth inhibition in A431 cells and good biocompatibility with HaCaT cells. Histopathological studies showed that the efficacy of the optimized MOF gels improved as the epithelial cells manifested modest hyperplasia, nuclear pleomorphism, and dyskeratosis. Additionally, immunohistochemistry and protein expression studies demonstrated the improved effectiveness of the 5-FU@ZIF-8-SDG MOFs, which displayed a considerable reduction in the expression of Bcl-2 protein. Overall, the developed MOF gels showed good potential for the targeted delivery of multifunctional MOFs in topical formulations for treating BCC cancer.

Porous organic frameworks (POFs) have become a highly sought-after research domain that offers a promising avenue for developing cutting-edge nanostructured materials, both in their pristine state and when subjected to various chemical and structural modifications. Metal-organic frameworks, covalent organic frameworks, and hydrogen-bonded organic frameworks are examples of these emerging materials that have gained significant attention due to their unique properties, such as high crystallinity, intrinsic porosity, unique structural regularity, diverse functionality, design flexibility, and outstanding stability. This review provides an overview of the state-of-the-art research on base-stable POFs, emphasizing the distinct pros and cons of reticular framework nanoparticles compared to other types of nanocluster materials. Thereafter, the review highlights the unique opportunity to produce multifunctional tailoring nanoparticles to meet specific application requirements. It is recommended that this potential for creating customized nanoparticles should be the driving force behind future synthesis efforts to tap the full potential of this multifaceted material category.

Immunogenic cell death (ICD) is a novel cell death mechanism that activates and regulates the immune system against cancer. However, its prognostic value in liver cancer remains unclear. Here, several algorithms such as correlation analysis, Cox regression analysis, and Lasso regression analysis were carried out to evaluate the prognostic value of ICD-related genes in patients with liver cancer. Three ICD-related prognostic genes, the prion protein gene (PRNP), dynamin 1-like gene (DNM1L), and caspase-8 (CASP8), were identified and used to construct a risk signature. Patients with liver cancer were categorized into high- and low-risk groups using the ICD-related signature. Subsequently, a multivariate regression analysis revealed that the signature was an independent risk factor in liver cancer [hazard ratio (HR) = 6.839; 95% confidence interval (CI) = 1.625-78.785]. Patient survival was also predicted using the risk model, with area under the curve values of 0.75, 0.70, and 0.69 for 1-, 3-, and 5-year survival, respectively. Finally, a prognostic nomogram containing the clinical characteristics and risk scores of patients was constructed. The constructed ICD-related signature could serve as a prognostic and immunotherapeutic biomarker in liver cancer.

Cancer immunotherapy has been a revolutionary cancer treatment modality because it can not only eliminate primary tumors but also prevent metastases and recurrent tumors. Immunogenic cell death (ICD) induced by various treatment modalities, including chemotherapy, phototherapy, and radiotherapy, converts dead cancer cells into therapeutic vaccines, eliciting a systemic antigen-specific antitumor. However, the outcome effect of cancer immunotherapy induced by ICD has been limited due to the low accumulation efficiency of ICD inducers in the tumor site and concomitant damage to normal tissues. The boom in smart nanomaterials is conducive to overcoming these hurdles owing to their virtues of good stability, targeted lesion site, high bioavailability, on-demand release, and good biocompatibility. Herein, the design of targeted nanomaterials, various ICD inducers, and the applications of nanomaterials responsive to different stimuli, including pH, enzymes, reactive oxygen species, or dual responses are summarized. Furthermore, the prospect and challenges are briefly outlined to provide reference and inspiration for designing novel smart nanomaterials for immunotherapy induced by ICD.

Rapamycin has great potential in the antitumor application, but its therapeutic effect is seriously affected by poor water solubility, targeting ability, and low bioavailability. Here, we constructed a novel composite nanomaterial with PCN-224 as a drug carrier and loaded rapamycin, named R@BP@HA. The nanoplate not only improves targeting, but also synergizes rapamycin with PCN-224 to effectively promote tumor cell apoptosis, which subsequently causes immunogenic cell death (ICD), and shows strong therapeutic effect in 4T1 breast cancer model. The treatment effect depends on three main points:(i)Proapoptotic effect of rapamycin on tumor cells;(ii)ROS production by PCN-224-mediated photodynamic therapy;(iii)ICD induced DC maturation, increased immune response and promoted T cell proliferation and differentiation. This nanoplate offers potential antitumor efficacy in combination with chemotherapy, photodynamic therapy, and immunotherapy.