Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

The application of combinational therapy makes up for the limitation of monotherapy and achieves superior treatment against cancer. However, the combinational therapy remains restricted by the poor tumor‐specific delivery and the abscopal effect. Herein, reactive oxygen species (ROS)‐responsive PEGylated bilirubin nanoparticles (BRNPs) are developed to encapsulate two glutathione‐activatable drugs, including dimer‐7‐ethyl‐10‐hydroxycamptothecin (d‐SN38) and dimer‐lonidamine (d‐LND). Dimerization of the drugs significantly increases the drug loading capacity and the encapsulation efficiency of nanoparticles. With the assistance of iRGD peptide (cRGDKGPDC), the cellular uptake of BRNPs is more than double when compared with the control. In response to high levels of intracellular ROS, d‐SN38 and d‐LND are rapidly released from nanoparticles (SL@BRNPs). Furthermore, the pharmacodynamic experiments verify combining SL@BRNPs with anti‐PD‐L1 antibody greatly inhibits the primary tumor of breast cancer, improves CD8+ T cells levels, and CD8+ T cells/Tregs ratios in the tumor. Additionally, it shows high immune memory effect and can prevent the growth of lung metastasis. Taken together, the strategy pioneers a new way for the rational design of nanoassemblies through the combination of activatable drug dimers and stimuli‐responsive drug release, and a successful application of novel drug delivery systems in combination with the immune checkpoint blockade antibody.     

Transformable Nanoparticle‐Enabled Synergistic Elicitation and Promotion of Immunogenic Cell Death for Triple‐Negative Breast Cancer Immunotherapy

Although cisplatin‐based neoadjuvant chemotherapy is an efficient therapy approach for triple‐negative breast cancer (TNBC), it has dismal prognosis and modestly improved survival benefit. Here, a synergistic immunotherapy of TNBC premised on the elicitation and promotion of immunogenic cell death (ICD) response, through a transformable nanoparticle‐enabled approach for contemporaneous delivery of cisplatin, adjudin, and WKYMVm is reported. The nanoparticles can sequentially respond to matrix metalloproteinases‐2, pH, and glutathione to achieve structural transformation with the advantages of optimal size change, efficient drug delivery, and well‐controlled release. Cisplatin and adjudin can synergistically amplify reactive oxygen species (ROS) cascade and eventually increase the formation of hydrogen peroxide and downstream highly toxic ROS like ?OH, which can elicit ICD response by mechanisms of endoplasmic reticulum stress, apoptotic cell death, and autophagy. WKYMVm can further promote anti‐TNBC immunity by activation of formyl peptide receptor 1 to build stable interactions between dendritic cells and dying cancer cells. Thus, the nanoparticles achieve significant primary tumor regression and pulmonary metastasis inhibition as well as a remarkable survival benefit, with boosting of the innate and adaptive anti‐TNBC immunity.     

Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

The condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.     

Dual‐Targeting to Cancer Cells and M2 Macrophages via Biomimetic Delivery of Mannosylated Albumin Nanoparticles for Drug‐Resistant Cancer Therapy

Multidrug resistance (MDR) is an issue that is not only related to cancer cells but also associated with the tumor microenvironments. MDR involves the complicated cancer cellular events and the crosstalk between cancer cells and their surroundings. Ideally, an effective system against MDR cancer should take dual action on both cancer cells and tumor microenvironments. The authors find that both the drug‐resistant colon cancer cells and the protumor M2 macrophages highly express two nutrient transporters, i.e., secreted protein acidic and rich in cysteine (SPARC) and mannose receptors (MR). By targeting SPARC and MR, a system can act on both cancer cells and M2 macrophages. Herein the authors develop a mannosylated albumin nanoparticles with coencapsulation of different drugs, i.e., disulfiram/copper complex (DSF/Cu) and regorafenib (Rego). The results show that combination therapy of DSF/Cu and Rego efficiently inhibits the growth of drug‐resistant colon tumor, and the combination has not been reported yet for use in anticancer treatment. The system significantly improves the treatment outcomes in the animal model bearing drug‐resistant tumors. The therapeutic mechanisms involve enhanced apoptosis, upregulation of intracellular ROS, anti‐angiogenesis, and tumor‐associated macrophage “re‐education.” This strategy is characterized by dual targeting to and the simultaneous action on cancer cells and M2 macrophages, with biomimetic codelivery of a novel drug combination.     

Combination of Bacterial‐Photothermal Therapy with an Anti‐PD‐1 Peptide Depot for Enhanced Immunity against Advanced Cancer

Photothermal therapy (PTT) is a promising cancer treatment, but it has so far proven successful only with relatively small subcutaneous tumors in animal models. Treating larger tumors (≈200 mm³) is challenging because most PTT materials do not efficiently reach the hypoxic, avascular center of tumors, and the immunosuppressive tumor microenvironment prevents T cells from fighting against residual tumor cells, thereby allowing recurrence and metastasis. Here, the widely used PTT material polydopamine is coated on the surface of the facultative anaerobe Salmonella VNP20009, which can penetrate deep into larger tumors. The coated bacteria are intravenously injected followed by near‐infrared laser irradiation at the tumor site, combined with a local inoculation of phospholipid‐based phase separation gel containing the anti‐programmed cell death‐1 peptide AUNP‐12. The gel releases AUNP‐12 sustainably during 42 days, maintaining the tumor microenvironment as immunopermissive. Using a mouse model of melanoma, this triple combination of biotherapy, PTT, and sustainable programmed cell death‐1 (PD‐1) blockade shows high efficiency on eliciting robust antitumor immune responses and eliminating relatively large tumors in 50% of animals within 80 days. Thus, the results shed new light on a previously unrecognized immunological facet of bacteria‐mediated therapy, and this innovative triple therapy may be a powerful cancer immunotherapy tool.     

A Self‐Transformable pH‐Driven Membrane‐Anchoring Photosensitizer for Effective Photodynamic Therapy to Inhibit Tumor Growth and Metastasis

Poor tumor selectivity and short life span of reactive oxygen species (ROS) are two major challenges in photodynamic therapy (PDT). In this study, a self‐transformable pH‐driven membrane anchoring photosensitizer (pHMAPS) is used to realize tumor‐specific accumulation and in situ PDT on tumor cell membrane to maximize the therapeutic potency. It is found that pHMAPS was able to form α‐helix structure under acidic condition (pH 6.5 or 5.5), while remain random coil at normal pH of 7.4. This pH‐driven secondary structure switch enables the successful insertion of pHMAPS into membrane lipid bilayer, especially for cancerous cell membrane in the acidic tumor microenvironment. Under laser irradiation, cytotoxic ROS is generated in the immediate vicinity of cell membrane, resulting in superior cell killing effect in vitro and significant inhibition of tumor growth in vivo. Importantly, benefited from this membrane‐specific PDT, tumor growth‐induced hepatic, pulmonary, as well as osseous metastases of breast cancer cells are also retarded after PDT treatment. Thus, the membrane localized PDT by pHMAPS provides a simple but effective strategy to enhance the medical performance of photosensitizing agents in cancer therapy.     

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.     

Schottky Heterojunction Realizes In Situ Vaccine-Like Antitumor Efficacy and Microenvironment Remodeling Upon Near-Infrared Laser Response in Cold Tumors

Cold tumor is one of the most refractory tumors due to its low immunogenicity and absence of T cell infiltration. The immunotherapeutic effect of near-infrared (NIR) responsive nanomaterials on tumors is far from satisfactory. Herein, ultrasmall γ-MnO₂ nanodots are anchored on the intrinsic metallic Ti₃C₂(OH)₂, modified with bovine serum albumin, to realize a Schottky heterojunction (labeled as TC-MnO₂@BSA), which can be utilized to reshape the cold tumor microenvironment (TME) through in situ vaccine-like antitumor effect. The Schottky heterojunction endows TC-MnO₂@BSA with improved photothermal conversion and reactive oxygen species (ROS) generation. Excess ROS and heat lead to tumor immunogenic death (ICD) and abundant damaged double-strain DNA releasing into TME, coordinated with TC-MnO₂@BSA-derived Mn²⁺, magnifying the cGAS-STING signaling pathway, eventually promoting antigen presentation of dendritic cells and infiltration of T cells. Such a NIR-activated nanovaccine can achieve complete ablation of tumors while robust activating systemic antitumor immune response. Furthermore, it inhibits the growth of abscopal tumors through dramatically “heating” their cold TME. This work introduces a universal strategy to magnify the photothermal and immune adjuvant effect through the gain of Schottky heterostructure, as a novel paradigm to construct the multifunctional in situ nanovaccine.     

Bio‐Hybrid Tumor Cell‐Templated Capsules: A Generic Formulation Strategy for Tumor Associated Antigens in View of Immune Therapy

For the development of effective anti‐cancer vaccines, tumor associated antigens need to be internalized by antigen presenting cells alongside specific co‐stimulatory signals. Interestingly, relative to soluble antigens, nano‐ and micro‐particulate antigens are much better presented to CD8 T cells, a crucial step in the induction of cytotoxic T cells that can eliminate malignant cells. In this regard, a generic strategy to encapsulate cancer cell derived proteins into a particulate delivery system would be of high interest. Here we present a versatile approach to incorporate cancer cell proteins into polymeric capsules using the cells themselves as templates for layer‐by‐layer assembly of complimentary interacting species. After coating, the cells are killed by hypo‐osmotic treatment leading to bio‐hybrid capsules loaded with cell lysate. Particular focus is devoted in this work on choosing the optimal coating components and conditions to maximize cell membrane integrity during the coating process, minimize pre‐mature protein release and achieve optimal encapsulation of cell lysate upon lysis of the cells. To further underline the generic nature of our approach, we demonstrate that heat shock proteins, important immune‐activators, can be induced and encapsulated into the bio‐hybrid capsules.     

Cancer Cell Membrane‐Coated Gold Nanocages with Hyperthermia‐Triggered Drug Release and Homotypic Target Inhibit Growth and Metastasis of Breast Cancer

The cell‐specific targeting drug delivery and controlled release of drug at the cancer cells are still the main challenges for anti‐breast cancer metastasis therapy. Herein, the authors first report a biomimetic drug delivery system composed of doxorubicin (DOX)‐loaded gold nanocages (AuNs) as the inner cores and 4T1 cancer cell membranes (CMVs) as the outer shells (coated surface of DOX‐incorporated AuNs (CDAuNs)). The CDAuNs, perfectly utilizing the natural cancer cell membranes with the homotypic targeting and hyperthermia‐responsive ability to cap the DAuNs with the photothermal property, can realize the selective targeting of the homotypic tumor cells, hyperthermia‐triggered drug release under the near‐infrared laser irradiation, and the combination of chemo/photothermal therapy. The CDAuNs exhibit a stimuli‐release of DOX under the hyperthermia and a high cell‐specific targeting of the 4T1 cells in vitro. Moreover, the excellent combinational therapy with about 98.9% and 98.5% inhibiting rates of the tumor volume and metastatic nodules is observed in the 4T1 orthotopic mammary tumor models. As a result, CDAuNs can be a promising nanodelivery system for the future therapy of breast cancer.     

Four Birds with One Stone: A Multifunctional Polypeptide Nanocomposite to Unify Ferroptosis,Nitric Oxide,and Photothermia for Amplifying Antitumor Immunity

Tumor metastasis and relapse mainly results in therapy failure and becomes a big challenge in oncology. Immunogenic cell death (ICD) of tumors mediated immunotherapy (IT) is attracting widely for solving that problem although achieving sufficient ICD and strong immune response is challenging for nanoparticles-based cancer IT. Herein, a multifunctional polypeptide coordinate nanocomposite that possesses near infrared photothermia (PT) and responsive releases of nitric oxide (NO) and iron ions is constructed, which synergistically kills cancer cells and highly prohibits metastatic 4T1 cells invasion and migration by PT-boosted NO release and ferroptosis (FT). Remarkably, triple FT-NO-PT treatment amplifies the ICD effects and outperforms combo/monotherapy FT-PT and FT in cancer cells and tumors, which further activates dendritic cells maturation, and primed CD4⁺T and CD8⁺T cells immune responses and memory effects, playing four birds with one stone (i.e., FT-NO-PT-IT). The PCSFG-based FT-NO-PT not only fully eradicates 4T1 primary tumors, but also induces strong ICD, immune priming, and memory effects to reject rechallenged 4T1 tumors and inhibit malignant tumor metastasis, demonstrating synergistic amplified ICD effects with strong cell immunities and memory effects by a unified FT-NO-PT-IT.     

Inhibition of Immunosuppressive Tumors by Polymer‐Assisted Inductions of Immunogenic Cell Death and Multivalent PD‐L1 Crosslinking

Checkpoint blockade immunotherapies harness the host's own immune system to fight cancer, but only work against tumors infiltrated by swarms of preexisting T cells. Unfortunately, most cancers to date are immune‐deserted. Here, a polymer‐assisted combination of immunogenic chemotherapy and PD‐L1 degradation is reported for efficacious treatment in originally nonimmunogenic cancer. “Priming” tumors with backbone‐degradable polymer‐epirubicin conjugates elicits immunogenic cell death and fosters tumor‐specific CD8+ T cell response. Sequential treatment with a multivalent polymer‐peptide antagonist to PD‐L1 overcomes adaptive PD‐L1 enrichment following chemotherapy, biases the recycling of PD‐L1 to lysosome degradation via surface receptor crosslinking, and produces prolonged elimination of PD‐L1 rather than the transient blocking afforded by standard anti‐PD‐L1 antibodies. Together, these findings establish the polymer‐facilitated tumor targeting of immunogenic drugs and surface crosslinking of PD‐L1 as a potential new therapeutic strategy to propagate long‐term antitumor immunity, which might broaden the application of immunotherapy to immunosuppressive cancers.     

Copper(I) Phosphide Nanocrystals for In Situ Self‐Generation Magnetic Resonance Imaging‐Guided Photothermal‐Enhanced Chemodynamic Synergetic Therapy Resisting Deep‐Seated Tumor

Fe‐based Fenton agents can generate highly reactive and toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME) for chemodynamic therapy (CDT) with high specificity. However, the strict condition (lower pH environment: 3–4) of the highly efficient Fenton reaction limits its practical application in the clinic. Development of new CDT agents more suitable for TME is significant and challenging. A highly efficient Cu(I)‐based CDT agent, copper(I) phosphide nanocrystals (CP NCs), which is more adaptable to the pH value of TME than Fe‐based agents, thereby producing more ·OH to trigger the apoptosis of cancer cells, is prepared. Moreover, the excess glutathione (GSH) in TME can reduce the Cu(II) produced by a Fenton‐like reaction to Cu(I), further increasing the generation rate of ·OH and relieving tumor antioxidant ability. Furthermore, owing to their strong absorption in the NIR II region, CP NCs exhibit an excellent photothermal conversion effect, which can further improve the Fenton reaction. What is more, CP NCs can act as in situ self‐generation magnetic resonance imaging (MRI) agents owing to the generation of paramagnetic Cu(II) in response to excess H₂O₂ in the TME. These properties may open up the exploration of copper‐based materials in clinical application of self‐generation imaging‐guided synergetic treatment.     

Effective and Selective Anti‐Cancer Protein Delivery via All‐Functions‐in‐One Nanocarriers Coupled with Visible Light‐Responsive,Reversible Protein Engineering

Efficient intracellular delivery of protein drugs and tumor‐specific activation of protein functions are critical toward anti‐cancer protein therapy. However, an omnipotent protein delivery system that can harmonize the complicated systemic barriers as well as spatiotemporally manipulate protein function is lacking. Herein, an “all‐functions‐in‐one” nanocarrier doped with photosensitizer (PS) is developed and coupled with reactive oxygen species (ROS)‐responsive, reversible protein engineering to realize cancer‐targeted protein delivery, and spatiotemporal manipulation of protein activities using long‐wavelength visible light (635 nm) at low power density (5 mW cm^?2). Particularly, RNase A is caged with H₂O₂‐cleavable phenylboronic acid to form 4‐nitrophenyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)benzyl carbonate (NBC)‐modified RNase (RNBC), which is encapsulated in acid‐degradable, ketal‐crosslinked PEI (KPEI)‐based nanocomplexes (NCs) coated with PS‐modified hyaluronic acid (HA). Such NCs harmonize the critical processes for protein delivery, wherein HA coating renders NCs with long blood circulation and cancer cell targeting, and KPEI enables endosomal escape as well as acid‐triggered intracellular RNBC release. Tumor‐specific light irradiation generates H₂O₂ to kill cancer cells and restore the protein activity, thus achieving synergistic anti‐cancer efficacy. It is the first time to photomanipulate protein functions by coupling ROS‐cleavable protein caging with PS‐mediated ROS generation, and the “all‐functions‐in‐one” nanocarrier represents a promising example for the programmed anti‐cancer protein delivery.     

Theranostic Prodrug Vesicles for Reactive Oxygen Species‐Triggered Ultrafast Drug Release and Local‐Regional Therapy of Metastatic Triple‐Negative Breast Cancer

A reactive oxygen species (ROS)‐activatable doxorubicin (Dox) prodrug vesicle (RADV) is presented for image‐guided ultrafast drug release and local‐regional therapy of the metastatic triple‐negative breast cancer (TNBC). RADV is prepared by integrating a ROS‐activatable Dox prodrug, a poly(ethylene glycol) (PEG)‐modified photosensitizer pyropheophorbide‐a, an unsaturated phospholipid 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine, and cholesterol into one single nanoplatform. RADV is of extremely high drug loading ratio (27.5 wt%) by self‐assembly of the phospholipid‐mimic Dox prodrug into the liposomal bilayer membrane. RADV displays good colloidal stability to prevent premature drug leakage during the blood circulation and inert photochemotoxicity to avoid nonspecific side effect. RADV passively accumulates at tumor site through the enhanced permeability and retention effect when administrated systemically. Once deposited at the tumor site, RADV generates fluorescent and photoacoustic signals to guide near‐infrared (NIR) laser irradiation, which can induce localized ROS generation, not only to trigger prodrug activation and ultrafast drug release but also conduct photodynamic therapy in a spatiotemporally controlled manner. In combination with NIR laser irradiation, RADV efficiently inhibits the tumor growth and distant metastasis of TNBC. Local‐regional tumor therapy using intelligent theranostic nanomedicine might provide an alternative option for highly efficient treatment of the metastatic TNBC.     

Covalent Organic Framework‐Supported Molecularly Dispersed Near‐Infrared Dyes Boost Immunogenic Phototherapy against Tumors

Photodynamic therapy (PDT) mediated by near‐infrared (NIR) dyes is a promising cancer treatment modality; however, its use is limited by significant challenges, such as hypoxic tumor microenvironments and self‐quenching of photosensitizers. These challenges hamper its utility in inducing immunogenic cell death (ICD) and triggering potent systemic antitumor immune responses. This study demonstrates that molecular dispersion of NIR dyes in nanocarriers can significantly enhance their ability to produce reactive oxygen species and potentiate synergistic PDT and photothermal therapy against tumors. Specifically, NIR dye indocyanine green (ICG) can be spontaneously adsorbed to covalent organic frameworks (COFs) via π–π conjugations to prevent intermolecular stacking interactions. Then, ICG‐loaded COFs are ultrasonically exfoliated and coated with polydopamine (PDA) to construct a new phototherapeutic agent ICG@COF‐1@PDA with enhanced efficacy. In conjunction with ICG@COF‐1@PDA, a single round of NIR laser irradiation can induce obvious ICD, elicit antitumor immunity in colorectal cancer, and yield 62.9% inhibition of untreated distant tumors. ICG@COF‐1@PDA also exhibits notable phototherapeutic efficacy against 4T1 murine breast to lung metastasis, a spontaneous metastasis mode for triple‐negative breast cancers (TNBCs). Overall, this study reveals a novel nanodelivery system for molecular dispersion of NIR dyes, which may present new therapeutic opportunities against primary and metastatic tumors.     

Boosting H2O2‐Guided Chemodynamic Therapy of Cancer by Enhancing Reaction Kinetics through Versatile Biomimetic Fenton Nanocatalysts and the Second Near‐Infrared Light Irradiation

Fenton reaction–based chemodynamic therapy (CDT) has attracted considerable attention for tumor treatment, because the Fenton reaction can degrade endogenous H₂O₂ within the tumor to form reactive oxygen species (ROS) to kill cancer cells. The kinetics of the Fenton reaction has significantly influenced its treatment efficacy. It is crucial to enhance the reaction kinetics at the maximum H₂O₂ concentration to quickly produce vast amounts of ROS to achieve treatment efficacy, which to date, has not been realized. Herein, reported is an efficacious CDT treatment of breast cancer using biomimetic CS‐GOD@CM nanocatalysts, which are rationally designed to significantly boost the Fenton reaction through improvement of H₂O₂ concentration within tumors, and application of the second near‐infrared (NIR‐II) light irradiation at the maximum concentration, which is monitored by photoacoustic imaging. The biomimetic nanocatalysts are composed of ultra‐small Cu_2?xSe (CS) nanoparticles, glucose oxidase (GOD), and tumor cell membrane (CM). The nanocatalysts can be retained in tumor for more than two days to oxidize glucose and produce an approximately 2.6‐fold increase in H₂O₂ to enhance the Fenton reaction under the NIR‐II irradiation. This work demonstrates for the first time the CDT treatment of cancer enhanced by the NIR‐II light.     

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.     

Reversing Immunosuppression in Hypoxic and Immune-Cold Tumors with Ultrathin Oxygen Self-Supplementing Polymer Nanosheets under Near Infrared Light Irradiation

Solid tumors are characterized by a hypoxic and immunologically “cold” microenvironment that dramatically limits the therapeutic outcomes of immunotherapy. Thus, strategies and materials that are capable of reversing immunosuppression in immune-cold tumors are highly desired. Herein, it is reported that oxygen (O₂) self-supplementing conjugated microporous polymer nanosheets can be utilized to elicit a robust antitumor T cell immune response in the hypoxic and immunosuppressive tumor microenvironment. The ultrathin nanosheets can generate O₂ through the water splitting reaction and produce massive reactive oxygen species (ROS) under near infrared light irradiation. Meanwhile, the unique photothermal property of the conjugated polymer nanosheets generates hyperthermia under irradiation. Consequently, they are able to maximize the immunogenic cell death (ICD) performance by inducing adequate damage-related molecular patterns in hypoxic tumors. Other than fostering T cell infiltration by the elicited ICD, the loaded indoleamine 2,3-dioxygenase in nanosheets can reverse the immunosuppression and empower ICD effect for efficient T cells priming. In vivo experiments conclusively prove that the designed polymer nanosheets exhibit great potential for tumor eradication, metastasis prevention, as well as long-term survival. Such a photocatalytic platform opens up new paths for reversing immunosuppression in immune-cold tumors and broadens the application of polymer-based nanosheets for cancer therapy.     

A Biocompatible Free Radical Nanogenerator with Real‐Time Monitoring Capability for High Performance Sequential Hypoxic Tumor Therapy

Hypoxic microenvironment severely reduces therapeutic efficacy of oxygen‐dependent photodynamic therapy in solid tumor due to the hampered cytotoxic oxygen radicals generation. Herein, a biocompatible nanoparticle (NP) is developed by combining bovine serum albumin, indocyanine green (ICG), and an oxygen‐independent radicals generator (AIPH) for efficient sequential cancer therapy, denoted as BIA NPs. Upon near‐infrared irradiation, the photothermal effect generated by ICG will induce rapid decomposition of AIPH to release cytotoxic alkyl radicals, leading to cancer cell death in both normoxic and hypoxic environments. Moreover, such nanosystem provides the highest AIPH loading capacity (14.9%) among all previously reported radical nanogenerators (generally from 5–8%). Additionally, the aggregation‐quenched fluorescence of ICG molecules in the NPs can be gradually released and recovered upon irradiation enabling real‐time drug release monitoring. More attractively, these BIA NPs exhibit remarkable anticancer effects both in vitro and in vivo, achieving 100% tumor elimination and 100% survival rate among 50 days treatment. These results highlight that this albumin‐based nanoplatform is promising for high‐performance cancer therapy circumventing hypoxic tumor environment and possessing great potential for future clinical translation.