Rational Design of Tumor Microenvironment‐Activated Micelles for Programed Targeting of Breast Cancer Metastasis

The poor drug delivery to primary and metastatic tumors of breast cancer remains a great challenge for effective antimetastasis therapy. Herein, a tumor microenvironment‐activated cabazitaxel micelles decorated with legumain‐specific melittin (TCM‐legM) are rationally designed for programed targeting of breast cancer metastasis. TCM‐legM is quiescent in blood circulation, but can be specifically activated by the highly expressed legumain in tumor microenvironments to improve their specific targeting and deep penetrating to primary or metastatic tumors. Thereafter, the activated TCM‐legM can be efficiently internalized by cancer cells and motivate the rapid pH‐responsive drug release for antimetastasis therapy. In metastatic 4T1 breast cancer cells, TCM‐legM presents significant inhibition on the proliferation, migration, and invasion activities. In vivo, TCM‐legM can be effectively delivered to both primary and metastatic tumors of breast cancer with deep tumor penetration and efficient cellular internalization, thereby resulting in a notable reduction of tumor growth and producing a 93.4% suppression of lung metastasis. Taken together, the rationally designed TCM‐legM can provide an intelligent drug delivery strategy to enhance the medical performance on treating breast cancer metastasis.     

Emerging Approaches of Cell‐Based Nanosystems to Target Cancer Metastasis

Cancer metastasis accounts for the high mortality of cancer‐related deaths and the therapy is greatly challenged by the limited drug delivery efficiency. Inspired by the essential role of culprit cancer cells and versatile accessory cells during cancer metastasis, diverse cell‐based nanosystems (CBNs) are emerging as attractive and encouraging drug delivery platforms to target cancer metastasis. Herein, the authors focus on the emerging strategies of versatile CBNs that synergistically combine the merit of source cells and nanoparticles for antimetastasis therapy. CBNs are usually comprised of natural nanosized vesicles, cell membrane camouflaged nanoparticles, and bioengineered living cell vehicles. The authors discuss the rationality and advances of various CBNs in targeting different stages of cancer metastasis, including primary tumor, circulating tumor cells (CTCs), and distant metastasis as well as the tumor immune microenvironments (TIM). On this basis, this review provides some feasible perspectives on designing CBNs to enhance the drug delivery efficiency for treating cancer metastasis.     

Designer Exosomes for Active Targeted Chemo‐Photothermal Synergistic Tumor Therapy

Exosomes, naturally derived nanovesicles secreted from various cell types, can serve as an effective platform for the delivery of various cargoes, because of their intrinsic ability such as long blood circulation and immune escapinge. However, unlike conventional synthetic nanoparticles, drug release from exosomes at defined targets is not controllable. Moreover, endowing exosomes with satisfactory cancer‐targeting ability is highly challenging. Here, for the first time, a biological and synthetic hybrid designer exosome is described with photoresponsive functionalities based on a donor cell‐assisted membrane modification strategy. Practically, the designer exosome effectively accumulates at target tumor sites via dual ligand‐mediated endocytosis. Then the localized hyperthermia induced by the conjunct gold nanorods under near‐infrared irradiation impacts the permeability of exosome membrane to enhance drug release from exosomes, thus inhibiting tumor relapse in a programmable manner. The designer exosome combines the merits of both synthetic materials and the natural nanovesicles. It not only preserves the intrinsic functionalities of native exosome, but also gains multiple abilities for efficient tumor targeting, controlled release, and thermal therapy like synthetic nanocarriers. The versatile designer exosome can provide functional platforms by engineering with more multifarious functionalities from synthetic materials to achieve individualized precise cancer therapy in the future.     

pH/Cathepsin B Hierarchical‐Responsive Nanoconjugates for Enhanced Tumor Penetration and Chemo‐Immunotherapy

An ideal cancer nanomedicine should precisely deliver therapeutics to its intracellular target within tumor cells. However, the multiple biological barriers seriously hinder their delivery efficiency, leading to unsatisfactory therapeutic outcome. Herein, pH/cathepsin B hierarchical‐responsive nanoconjugates (HRNs) are reported to overcome these barriers by sequentially responding to extra‐ and intracellular stimuli in solid tumors for programmed delivery of docetaxel (DTX). The HRNs have stable nanostructures (≈40 nm) in blood circulation for efficient tumor accumulation, while the tumor extracellular acidity induces the rapid dissociation of HRNs into polymer conjugates (≈5 nm), facilitating the deep tumor penetration and cellular internalization. After being trapped into the lysosomes, the conjugates are cleaved by cathepsin B to release bioactive DTX into cytoplasm and inhibit cell proliferation. In addition to the direct inhibition effect, HRNs can trigger the in vivo antitumor immune responses via the immunogenic modulation of tumor cells, activation of dendritic cells (DCs), and generation of cytotoxic T‐cell responses. By employing a combination with α‐PD‐1 (programmed cell death 1) therapy, synergistic antitumor efficacy is achieved in B16 expressing ovalbumin (B16OVA) tumor model. Hence, this strategy demonstrates high efficiency for precise intracellular delivery of chemotherapeutics and provides a potential clinical candidate for cancer chemo‐immunotherapy.     

Nanopoxia: Targeting Cancer Hypoxia by Antimonene-Based Nanoplatform for Precision Cancer Therapy

Most anticancer drugs with broad toxicities are systematically administrated to cancer patients and their distribution in tumors is extremely low owing to hypoxia, which compromises the therapeutic efficacies of these cancer drugs. Consequently, a preponderant proportion of cancer drugs is distributed in off-target-healthy tissues, which often causes severe adverse effects. Precision cancer therapy without overdosing patients with drugs remains one of the most challenging issues in cancer therapy. Here, a novel concept of nanopoxia is presented, which is a tumor-hypoxia-based photodynamic nanoplatform for the release of therapeutic agents to achieve precision cancer therapy. Under tumor hypoxia, exposure of tumors to laser irradiation induces the fracture of polymer outer shell and produces anticancer reactive oxygen species, and switches 2D antimonene (Sb) nanomaterials to cytotoxic trivalent antimony to synergistically kill tumors. In preclinical cancer models, delivery of Sb nanomaterials to mice virtually ablates tumor growth without producing any detectable adverse effects. Mechanistically, the tumor hypoxia-triggered generation of trivalent antimony displays direct damaging effects on cancer cells and suppression of tumor angiogenesis. Together, the study provides a proof-of-concept of hypoxia-based precision cancer therapy by developing a novel nanoplatform that offers multifarious mechanisms of cancer eradication.     

Endogenous Stimuli-Activatable Nanomedicine for Immune Theranostics for Cancer

Cancer immunotherapy has witnessed significant advances in the past decade, however challenges associated with immune-related adverse effects and immunosuppressive tumor microenvironment, have hindered their clinical application. Stimuli-activatable nanomedicines hold great potential for improving the efficiency of cancer immunotherapy and minimizing the side effects via tumor-specific accumulation, controllable drug release profile, and combinational therapy by integrating multiple therapeutic regimens. In this review, the recent advances of stimuli-activatable nanomedicines for cancer immunotherapy are first described, with particular focus on endogenous stimuli including pH, glutathione, reactive oxygen species, and excessive enzymes within the tumor microenvironment. Then, the endogenous stimuli-activatable nanomedicines that target tumor cells, immune cells, or periphery immune systems for eliciting sustained systemic immune activation and modulating the immunosuppressive tumor microenvironment, are described. Next, the general mechanisms underlying nanomedicine-based immunotherapy by eliciting anti-tumor immune responses and overcoming immunologic tolerance are described. Further, the emerging application of bioimaging techniques for monitoring immune response and evaluating therapy performance is described. Finally, the authors’ perspectives are provided for the clinical translation of nanomedicine-based cancer immunotherapy.     

Functional Nanomaterials Optimized to Circumvent Tumor Immunological Tolerance

Advances in cancer immunology have revealed that immunological tolerance, which is characterized by low immunogenicity, insufficient antigen presentation, and low T lymphocyte infiltration, increases the expression of inhibitory receptors and cytokines in tumors. These features make it possible for tumor cells to easily escape attack by immune cells. Nanomaterials, with unique properties such as ultrasmall size, unique surface characteristics, and multivalent effects, have attracted an increasing amount of attention in the regulation of the immunological microenvironment of tumors. In this review, the use of functional nanomaterials to reverse immunological tolerance in tumors is examined, including the use of nanomaterials for efficient cancer vaccines, checkpoint blockade delivery, cytokine delivery, artificial antigen presentation cells, and adoptive cell therapy. The benefits and challenges of using nanomaterials to circumvent the immunological tolerance of tumors are also discussed.     

Unraveling and Overcoming Platinum Drug-Resistant Cancer Tumors with DNA Nanostructures

All chemotherapeutic treatments worldwide (>50%) use platinum-based compounds. Despite their clinical success, an increasing number of platinum drug-resistant tumors are reported, limiting the therapeutic application of these compounds. While various kinds of strategies are pursued to circumvent resistances, there remains a lack of understanding of how cancer cells develop platinum drug resistances. Within this study, the involvement of the DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) in the occurrence of platinum drug resistance is directly visualized in living cells by a DNA tetrahedron-based molecular probe. Capitalizing on this biochemical insight, the suppression of the expression of APE1 in cancer cells is realized using a DNA tetrahedron-based RNA interference technique, presenting a novel strategy to overcome platinum drug resistance. This study presents the first example of Pt(IV) complex loaded tumor aptamer-modified DNA tetrahedrons with an APE1 specific small interfering RNA (siRNA) strand for suppression of APE1 expression and therapeutic treatment of patient-derived platinum drug-resistant lung cancer tumors.     

Zwitterionic Polysulfamide Drug Nanogels with Microwave Augmented Tumor Accumulation and On‐Demand Drug Release for Enhanced Cancer Therapy

Zwitterionic polymers demonstrate as a class of antifouling materials with long blood circulation in living subjects. Despite extensive research on their antifouling abilities, the responsive zwitterionic polymers that can change their properties by mild outside signals are poorly explored. Herein, a sulfamide‐based zwitterionic monomer is developed and used to synthesize a series of polysulfamide‐based (poly (2‐((2‐(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide (PMEDAPA)) nanogels as drug carriers for effective cancer therapy. PMEDAPA nanogels are proved to exhibit prolonged blood circulation without inducing the accelerated blood clearance phenomenon. Intriguingly, PMEDAPA nanogels can sensitively respond to hyperthermia by adjusting the crosslinker degree. After modified with transferrin (Tf), the nanogels (PMEDAPA‐Tf) achieve shielded tumor targeting at normothermia, while exhibiting recovered tumor targeting at hyperthermia, leading to enhanced tumor accumulation. Meanwhile, PMEDAPA‐Tf nanogels show superior penetration ability in 3D tumor spheroids and faster drug release at hyperthermia compared with that at normothermia. In combination with mild microwave heating (≈41 °C), the drug‐loaded PMEDAPA‐Tf nanogels show a pronounced tumor inhibition effect in a humanized orthotropic liver cancer model. Therefore, the study provides a novel hyperthermia‐responsive zwitterionic nanogel that can achieve augmented tumor accumulation and on‐demand drug release assisted with clinically used microwave heating for cancer therapy.     

Metal-Coordinated Adsorption of Nanoparticles to Macrophages for Targeted Cancer Therapy

Living cell-based drug delivery systems (LC-DDSs) are limited by adverse interactions between drugs and carrier cells, typically drug-induced toxicity to carrier cells and restriction of carrier cells on drug release. Here, a method is established to adsorb nanocarriers externally to living cells, thereby reducing cytotoxicity caused by drug uptake and realizing improved drug release at the disease site. It is found that a divalent metal ion-phenolic network (MPN) affords adhesion of poly (lactic-co-glycolic acid) nanoparticles onto macrophage (Mφ) surfaces with minimized intracellular uptake and no negative effect on cell proliferation. On this basis, an Mφ-DDS with doxorubicin-loaded nanoparticles on cell surface (DOX-NP@Mφ) is constructed. Compared to intracellular loading via endocytosis, this method well-maintains bioactivity (viability and migration chemotaxis) of the carrier cell. By virtue of the photothermal effect of MPN at the tumor site, DOX-NP-associated vesicles are liberated for improved chemotherapy. This facile, benign, and efficient method (ice bath, 2 min) for extracellular nanoparticle attachment and minimizing intracellular uptake provides a platform technology for LC-DDS development.     

A Microenvironment Dual-Responsive Nano-Drug Equipped with PD-L1 Blocking Peptide Triggers Immunogenic Pyroptosis for Prostate Cancer Self-Synergistic Immunotherapy

Induction of immunogenic cell death (ICD) in tumor combined with immune checkpoint blockade (ICB) therapy is widely developed to improve the efficacy of cancer immunotherapy. However, the current ICD induced based on apoptosis, i.e., immunogenic apoptosis, is often restricted in immunogenicity owing to the inflammatory quenching that occurs early in apoptosis. Recently, pyroptosis is demonstrated to be a more efficient ICD form, i.e., immunogenic pyroptosis. The cell contents released during pyroptosis can powerfully activate tumor immunogenicity. Herein, first, it is demonstrated that lower doses of epigenetic drug decitabine can increase GSDME expression in prostate cancer (PCa) RM-1 cells and successfully induce an apoptosis-pyroptosis transition after photodynamic therapy (PDT). Subsequently, a microenvironment dual-responsive nano-drug equipped with PD-L1 blocking peptide (TSD@LSN-D) is developed for self-synergistic cancer immunotherapy. The poorly immunogenic RM-1 PCa model confirm that the powerful antitumor immune response evoked by TSD@LSN-D not only can effectively inhibit the primary tumor but also form a long-term immune memory to prevent PCa recurrence and metastasis. To the best of authors’ knowledge, this work presents the first concept that promotes the apoptosis–pyroptosis transition after tumor PDT through epigenetic modulation. Furthermore, the powerful combination of immunogenic pyroptosis with ICB opens a new platform for PCa immunotherapy.     

Ly6Chi Monocytes Delivering pH‐Sensitive Micelle Loading Paclitaxel Improve Targeting Therapy of Metastatic Breast Cancer

Many immune cells are capable of homing to sites of disease and eradicating infections and abnormal cells. However, their efficacy is usually down‐regulated in tumor microenvironments and it is difficult to boost. It is presumed that the anticancer activity of immune cells can be improved by integrating an additional therapeutic modality such as chemotherapy into the cells. Here, Ly6C^hi monocytes armed with the paclitaxel (PTX)‐loading pH‐sensitive micelle (PM), termed as PM@MC, are prepared. The PM internalization does not significantly affect the properties of the host Ly6C^hi monocytes. In the 4T1 metastatic breast cancer mice model, PM@MCs home to both primary tumor and the lung metastasis foci. PM@MC exhibit 15‐fold higher intratumor PTX accumulation than the commercial PTX injection, and achieve a tumor inhibiting rate of 96.8% and a lung metastasis suppression rate of 99.2%. No significant change is recorded in histology of major organs and in hematological and biochemical parameters after PM@MC treatment. The pH‐sensitive micelle/Ly6C^hi monocyte drug delivery device thus has the application potential in the targeting therapy of breast cancer with metastasis.     

Long Circulation Red‐Blood‐Cell‐Mimetic Nanoparticles with Peptide‐Enhanced Tumor Penetration for Simultaneously Inhibiting Growth and Lung Metastasis of Breast Cancer

Limited blood circulation and poor tumor penetration are two main obstacles hampering the clinical translation of conventional nanosized drug delivery systems (NDDS). Here, red‐blood‐cell (RBC)‐mimetic nanoparticles (NPs) with long circulation and peptide‐enhanced tumor penetration for treating metastatic breast cancer are reported. The RBC‐mimetic NPs are composed of a paclitaxel (PTX)‐loaded polymeric core and a hydrophilic RBC vesicle shell. The RBC‐mimetic NPs display dramatically elongated blood circulation with an elimination half time of 32.8 h, 5.8‐fold higher than that of the parental polymeric NPs (i.e., 5.6 h). Moreover, the experimental results demonstrate that the tumor penetration ability of the RBC‐mimetic NPs can be significantly improved by coadministrating with a tumor‐penetrating peptide iRGD. Antitumor studies using a metastatic 4T1 breast tumor model show that RBC‐mimetic NPs in combination with iRGD significantly inhibit over 90% of the tumor growth and suppress 95% of the lung metastasis, much more efficient than PTX‐loaded polymer NP alone or the combination of polymer NPs and iRGD. The results reveal the importance of both long circulation and tumor penetration of nanosized drugs for efficient cancer therapy, which can provide a new insight for NDDS design.     

Bioinspired Nanoparticles with NIR‐Controlled Drug Release for Synergetic Chemophotothermal Therapy of Metastatic Breast Cancer

Optimal nanosized drug delivery systems (NDDS) require long blood circulation and controlled drug release at target lesions for efficient anticancer therapy. Red blood cell (RBC) membrane‐camouflaged nanoparticles (NPs) can integrate flexibility of synergetic materials and highly functionality of RBC membrane, endowed with many unique advantages for drug delivery. Here, new near‐infrared (NIR)‐responsive RBC membrane‐mimetic NPs with NIR‐activated cellular uptake and controlled drug release for treating metastatic breast cancer are reported. An NIR dye is inserted in RBC membrane shells, and the thermoresponsive lipid is employed to the paclitaxel (PTX)‐loaded polymeric cores to fabricate the RBC‐inspired NPs. The fluorescence of dye in the NPs can be used for in vivo tumor imaging with an elongated circulating halftime that is 12.3‐folder higher than that of the free dye. Under the NIR laser stimuli, the tumor cellular uptake of NPs is significantly enhanced to 2.1‐fold higher than that without irradiation. The structure of the RBC‐mimetic NPs can be destroyed by the light‐induced hyperthermia, triggered rapid PTX release (45% in 30 min). These RBC‐mimetic NPs provide a synergetic chemophotothermal therapy, completely inhibited the growth of the primary tumor, and suppress over 98% of lung metastasis in vivo, suggesting it to be an ideal NDDS to fight against metastatic breast cancer.     

Engineered Oxygen Factories Synergize with STING Agonist to Remodel Tumor Microenvironment for Cancer Immunotherapy

Immunotherapy is a revolutionary achievement in cancer treatment. However, inadequate immune cells infiltration in tumor microenvironment (TME) always leads to treatment failure. Moreover, hypoxic TME hampers normal functions of immune cells. Here, it is found that hypoxia suppresses the STING signaling and immune cells activation in the work. Remodeling tumor immune microenvironment and relieving hypoxia are thus essential for enhancing immunotherapy efficiency. Herein, a spirulina platensis (SP)-based magnetic biohybrid system is constructed as an oxygen factory and loaded with stimulator of interferon genes (STING) agonist ADU-S100 (ADU@Fe-SP) for tumor immunotherapy. Magnet-guided biohybrid SP can actively target tumor tissues and produce oxygen in situ through photosynthesis, which reverses the hypoxic TME and facilitates the function of immune cells. Besides, the targeted delivery of ADU-S100 can activate the STING/TBK1/IRF3 signaling and boost cytokines production in tumor and innate immune cells. The ADU@Fe-SP system thus induces efficient immune cells infiltration in TME, which efficiently inhibits tumor progression and significantly enhances anti-PD-1 therapy efficiency in SCC VII-bearing tumor xenograft. ADU@Fe-SP exerts antitumor effect in a STING-dependent manner by in vivo STING-knockout mice model. The efficiency of this immunotherapy strategy is also demonstrated in patient-derived xenograft model originating from oral cancer, showing great clinical potential.     

Virus‐Inspired Mimics Based on Dendritic Lipopeptides for Efficient Tumor‐Specific Infection and Systemic Drug Delivery

Herein, multifunctional mimics of viral architectures and infections self‐assembled from tailor‐made dendritic lipopeptides for programmed targeted drug delivery are reported. These viral mimics not only have virus‐like components and nanostructures, but also possess virus‐like infections to solid tumor and tumor cells. Encouragingly, the viral mimics provide the following distinguished features for tumor‐specific systemic delivery: i) stealthy surface to resist protein interactions and prolong circulation time in blood, ii) well‐defined nanostructure for passive targeting to solid tumor site, iii) charge‐tunable shielding for tumor extracellular pH targeting, iv) receptor‐mediated targeting to enhance tumor‐specific uptake, and v) supramolecular lysine‐rich architectures mimicking viral subcellular targeting for efficient endosomal escape and nuclear delivery. This bioinspired design make in vivo tumor suppression by drug‐loaded viral mimics against BALB/c mice bearing 4T1 tumor greatly exceed the positive control group (more than three times). More importantly, viral mimics hold great potentials to reduce side effects and decrease tumor metastasis after systemic administration.     

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

Glioblastoma multiforme is one of the most fatal intracranial tumors with no effective treatment. The drug concentration in tumor sites is usually insufficient to reach therapeutic levels, due to poor blood–brain‐barrier (BBB) permeability and short biological half‐life. Inspired by the proneness of those malignant tumors to brain metastasis, a brain metastatic tumor cell membrane‐coated nanocarrier with core–shell structure is constructed to cross BBB for imaging and photothermal therapy of early brain tumors. The cell membranes as the shell are extracted from different metastatic tumor cells, which endow the nanoparticles with BBB‐crossing ability and long circulation. Indocyanine green (ICG)‐loaded polymeric nanoparticle as the core allows fluorescence imaging and phototherapy of brain tumors. The as‐prepared biomimetic nanoparticles display superb BBB penetration and effective suppression of tumor growth. These findings suggest the biomimetic nanotechnology provides a new insight for the design of BBB‐crossing nanomaterials and is promising to treat brain diseases.     

The AIE-Active Dual-Cationic Molecular Engineering: Synergistic Effect of Dark Toxicity and Phototoxicity for Anticancer Therapy

The development of anticancer therapy is significant to human health but remains a huge challenge. Photodynamic therapy (PDT), inducing the synergistic mitochondrial dysfunction in cancer cells is a promising approach but suffer from the low efficiency in hypoxic microenvironment and deep-seated tumors. Herein, to improve the outcomes of PDT for cancer treatment, a series of red fluorophores consisting of dual-cationic triphenylphosphonium-alkylated pyridinium and (substituted) triphenylamine are prepared as organelle-targeting antitumor photosensitizers (PSs) with aggregation-induced emission characteristics. These PSs can selectively accumulate at the mitochondria or lysosomes of cancer cells with both dark- and photo-cytotoxicity, making them possess excellent killing effect on cancer cells and efficient inhibition of tumor growth in living mice. This study brings about new insight into the development of powerful cancer treatment.     

Tumor‐Microenvironment‐Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer

Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment‐adaptive nanoparticle co‐loading paclitaxel (PTX) and the anti‐metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH‐sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra‐tumor accumulation of both PTX and siRNA in the 4T1 tumor‐bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid‐triggered drug release in endo/lysosomes is achieved through the pH‐sensitive core. As a result, the MMP/pH dual‐sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor‐microenvironment‐adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.     

A NIR-II Fluorescent PolyBodipy Delivering Cationic Pt-NHC with Type II Immunogenic Cell Death for Combined Chemotherapy and Photodynamic Immunotherapy

Tumor immunotherapy has emerged as one of the most promising clinical techniques to treat cancer tumors. Despite its clinical application, the cancerous immunosuppressive microenvironment limits the therapeutic efficiency of the treatment. To generate a stronger immunogenic therapeutic effect, herein, a platinum complex for chemotherapy and a BODIPY photosensitizer for photodynamic therapy are encapsulated into multimodal type II immunogenic cell death (ICD) induce nanoparticles. As the platinum complex and the photosensitizer are able to induce type II ICD, an exceptionally strong immune response is observed in triple-negative breast cancer cells. While remaining stable and therefore poorly cytotoxic in the dark, the nanomaterial is found to quickly dissociate upon exposure to near-infrared light, causing a multimodal mechanism of action in cancer cells as well as multicellular tumor spheroids through combined chemotherapy, photodynamic therapy, and immunotherapy. The nanoparticles are found to nearly fully eradicate a triple-negative breast cancer tumor and therefore to strongly enhance the survival of tumor-bearing mice models using low drug and light doses.