Size/Charge Changeable Acidity‐Responsive Micelleplex for Photodynamic‐Improved PD‐L1 Immunotherapy with Enhanced Tumor Penetration

The checkpoint blockade‐based immunotherapy has recently emerged as a promising approach for tumor treatment, but its clinical implementation has been impeded by poor tumor penetration of the nanocarriers and activation of antitumor immune response. To overcome the obstacles, a tumor acidity‐responsive micellar nanocomplex co‐loaded with programmed death‐ligand 1 (PD‐L1)‐blockade siRNA and mitochondrion‐targeting photosensitizer for the synergistic integration of photodynamic therapy and immunotherapy is reported in the present study. The nanosystem is coated with long‐circulating polyethylene glycol (PEG) shells, which can be shed in response to the weakly acidic tumor microenvironment and lead to significant size reduction and increasing positive charge. These transitions facilitate penetration and uptake of nanocarriers against tumors. Subsequently, under the mild acidic endo/lysosome condition, the micellar nanocomplexes are rapidly protonated and disintegrated to release the PD‐L1‐blockade siRNA and photosensitizer through sponge effect. Results from in vitro and in vivo experiments collectively reveal that the nanosystem efficiently activates a photodynamic therapy‐induced immune response and silences immune resistance mediated by the checkpoint gene PD‐L1. In consequence, melanoma growth is inhibited and the recurrence rate is reduced via triggering systemic antitumor immune responses. This study offers an alternative strategy for the development of efficient antitumor immune 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.     

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.     

Treatment of Malignant Brain Tumor by Tumor‐Triggered Programmed Wormlike Micelles with Precise Targeting and Deep Penetration

The efficient and specific drug delivery to brain tumor is a crucial challenge for successful systemic chemotherapy. To overcome these limitations, here a tumor‐triggered programmed wormlike micelle is reported with precise targeting and deep penetration to treat malignant gliomas, which is composed of pH‐responsive mPEG‐b‐PDPA copolymer and bioreducible cyclic RGD peptide targeted cytotoxic emtansine (DM1) conjugates (RGD‐DM1). The RGD‐DM1 loaded nanoscaled wormlike micelles (RNW) exhibit nanometer‐sized wormlike assemblies with the transverse diameter of 21.3±1.8 nm and length within 60–600 nm, and the RGD targeting peptide in RNW is 4.2% in weight. RNW can be dissociated at intracellular acidic environments to release RGD‐DM1, and be further degraded into DM1 by cleavage of disulfide bonds in the reductive milieu. In particular, by exploiting the unique wormlike structure and the RGD targeting peptide modification, RNW can be endowed with obviously enhanced drug delivery to brain, precise targeting to brain tumor, deep penetration into tumor mass, and efficient internalization into glioma cells in a programmed manner, thereby surprisingly leading to an 88.9% inhibition on tumor progression in an orthotopic brain tumor model. Therefore, the properly designed RNW can provide a promising delivery platform for systemic chemotherapy of brain tumor.     

Light‐Activatable Assembled Nanoparticles to Improve Tumor Penetration and Eradicate Metastasis in Triple Negative Breast Cancer

Triple‐negative breast cancer (TNBC) is a kind of aggressive malignancy with fast metastatic behavior. Herein, a nanosystem loaded with a near‐infrared (NIR) agent is developed to achieve chemo‐photothermal combination therapy for inhibiting tumor growth and metastasis in TNBC. The NIR agent of ultrasmall sized copper sulfide nanodots with strong NIR light‐absorbing capability is entrapped into the doxorubicin‐contained temperature‐sensitive polymer‐based nanosystem by a self‐assembled method. The temperature sensitive nanoclusters (TSNCs) can significantly enhance the drug penetration depth and significantly kill the cancer cells under the near‐infrared laser irradiation. Importantly, it is plausible that the tumor penetrating nanosystem combined with NIR laser irradiation can prevent lung and liver metastasis via extermination of the cancer stem cells. The in vivo characteristics, evaluated by photoacoustic imaging, pharmacokinetics, and biodistribution, confirm their feasibility for tumor treatment owing to their long blood circulation time and high tumor uptake. Thanks to the high tumor uptake and highly potent antitumor efficacy, the doxorubicin‐induced cardiotoxicity can be avoided when the TSNC is used. Taken together, it is believed that the nanosystem has excellent potential for clinical translation.     

High‐Security Nanocluster for Switching Photodynamic Combining Photothermal and Acid‐Induced Drug Compliance Therapy Guided by Multimodal Active‐Targeting Imaging

High‐security nanoplatform with enhanced therapy compliance is extremely promising for tumor. Herein, using a simple and high‐efficient self‐assembly method, a novel active‐targeting nanocluster probe, namely, Ag₂S/chlorin e6 (Ce6)/DOX@DSPE‐mPEG₂₀₀₀‐folate (ACD‐FA) is synthesized. Experiments indicate that ACD‐FA is capable of specifically labeling tumor and guiding targeting ablation of the tumor via precise positioning from fluorescence and photoacoustic imaging. Importantly, the probe is endowed with a photodynamic “on‐off” effect, that is, Ag₂S could effectively quench the fluorescence of chlorin e6 (89.5%) and inhibit release of ¹O₂ (92.7%), which is conducive to avoid unwanted phototoxicity during transhipment in the body, and only after nanocluster endocytosed by tumor cells could release Ce6 to produce ¹O₂. Moreover, ACD‐FA also achieves excellent acid‐responsive drug release, and exhibits eminent chemo‐photothermal and photodynamic effects upon laser irradiation. Compared with single or two treatment combining modalities, ACD‐FA could provide the best cancer therapeutic effect with a relatively low dose, because it made the most of combined effect from chemo‐photothermal and controlled photodynamic therapy, and significantly improves the drug compliance. Besides, the active‐targeting nanocluster notably reduces nonspecific toxicity of both doxorubicin and chlorin e6. Together, this study demonstrates the potency of a newly designed nanocluster for nonradioactive concomitant therapy with precise tumor‐targeting capability.     

A Redox‐Triggered Bispecific Supramolecular Nanomedicine Based on Peptide Self‐Assembly for High‐Efficacy and Low‐Toxic Cancer Therapy

Polo‐like kinase 1 (PLK1) and polo‐like kinase 4 (PLK4) are closely associated with the progression of several cancers, and their bispecific inhibitors can kill tumor cells effectively. Herein, a redox‐responsive bispecific supramolecular nanomedicine based on the self‐assembly of a cyclic peptide, termed as C‐1, targeting both PLK1 and PLK4 as a potent anticancer agent is reported. C‐1 is a cyclic peptide in response to reducing agents such as glutathione (GSH), which is constructed by a combined approach of pharmacophore modeling, molecular docking, and reversible cyclization. After entering the cytosol of cancer cell, the disulfide linkage is reduced by intracellular GSH, with the resulting linear conformation self‐assembling into bispecific nanofibers. C‐1 can lead to apoptotic cell death by inducing caspase‐3 activation and PARP cleavage in HeLa cells. Moreover, it suppresses the growth of HeLa cells in cell assays, and inhibits the progression of HeLa cells‐induced xenografts in nude mice without inducing notable side effects. This work provides a successful example of developing the redox‐responsive bispecific nanomedicine for high‐efficacy and low‐toxic cancer therapy.     

Enhanced Penetration and Retention of CuS-Based Nanosystem Through NIR Light and In Situ Enzyme Response for Improved Tumor Therapy

The efficient way to increase the therapeutic efficacy of nanomedicines is by encouraging the penetration and enhancing the retention of nanoparticles at the tumor site. However, it is a serious dilemma that small nanoparticles can penetrate deep into the tumor tissue but easily be cleared into the surrounding tissues. In order to solve this dilemma, a smart nanosystem is created to address this problem, ensuring both the effective penetration of tiny nanoparticles (NPs) and their appropriate retention at the tumor site. CuS NPs that is modified with peptides are prepared facilely, and can aggregate in situ through the intermolecular crosslinking reaction catalyzed by the transglutaminase (TGase) abundantly expressed at the tumor site, resulting in an outstanding photothermal effect for tumor therapy. Upon NIR irradiation, the photothermal effect of CuS-K and CuS-Q induced the disintegration of liposomes and prompted the release of CuS-K, CuS-Q, and indocyanine green (ICG). Simultaneously, CuS-K and CuS-Q aggregated under the catalysis of TGase after being internalized by tumor cells to enhance photothermal therapy. The current study provides valuable inspiration to design nanomedicines with prolonged circulation time in the blood system, better penetration, and retention at the tumor site, and multimodal tumor therapy to achieve the desired therapeutic efficacy.     

Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma

O₂‐delivering nanosystems have been used to antagonize hypoxia‐induced tumor therapeutic resistance. However, short‐time oxygen storage is still a bottleneck for these O₂‐delivering nanosystems, which results in a decrease in blood circulation time and accumulation of oxygen in tumors, thus reducing the tumor therapeutic efficacy. Herein, a long‐term oxygen storage nanosystem (O₂‐PIr@Si@PDA) is designed to overcome hypoxia for the treatment of nasopharyngeal carcinoma. This nanosystem is constructed by using perfluorooctyl bromide (PFOB) core as the oxygen carrier, functionalized with an oxygen sensitive probe (Ir(III) complex) and subsequently enclosed with an ultrathin‐walled silica shell. Due to the silica shell, this nanosystem can store oxygen for longer than 7 days. The oxygen in the O₂‐PIr@Si@PDA nanosystem can be released quickly with the temperature‐responsive rupture of the silicon shell under near‐infrared (NIR) irradiation. The oxygen storage and release can be self‐monitored using the Ir(III) complex with its luminescence effect. As expected, this multifunctional nanosystem in combination with NIR irradiation not only inhibits tumor growth by alleviating hypoxia, but also enhances the effect of oxygen‐sensitized radiotherapy against nasopharyngeal carcinoma. Taken together, this study offers a novel strategy for designing long‐term oxygen storing nanosystem to relieve tumor hypoxia, thus improving the precise cancer therapeutic efficacy.     

Remotely Controlled Red Blood Cell Carriers for Cancer Targeting and Near‐Infrared Light‐Triggered Drug Release in Combined Photothermal–Chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus‐responsive, RBC‐based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near‐infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light‐induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC‐based cancer cell targeted drug delivery and light‐controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.     

Multifunctional and Stimuli‐Responsive Polydopamine Nanoparticle‐Based Platform for Targeted Antimicrobial Applications

The rising threat of antimicrobial resistance is a crisis of a global scale. If not addressed, it can lead to health care system problems worldwide. This warrants alternative therapeutic approaches whose mechanism of action starkly differs from conventional antibiotic‐based therapies. Here, a multifunctional and stimuli‐responsive (NIR laser‐activated) antimicrobial platform is engineered by combining the intrinsic photothermal capability and excellent biocompatibility of polydopamine nanoparticles (PdNPs), with the membrane targeting and lytic activities of an antimicrobial peptide (AMP). The resulting PdNP‐AMP nanosystem can specifically target and destabilize the mechanical integrity of the outer membrane of Escherichia coli, as measured using the atomic force microscope. Furthermore, the laser‐induced nano‐localized heating of PdNP—in close proximity to the already compromised bacterial envelope—induces further membrane damage. This results in a more efficient, laser‐activated, bacterial killing action of PdNP‐AMP. The antimicrobial platform developed in this work is shown to be effective against a drug‐resistant E. coli. Overall, this work highlights the advantage and strength of combining multiple and coordinated biocidal mechanisms, into one nanomaterial‐based system and its promise in treating drug‐resistant pathogens.     

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.     

Mesoporous Polydopamine Carrying Manganese Carbonyl Responds to Tumor Microenvironment for Multimodal Imaging‐Guided Cancer Therapy

Multifunctional nanodrugs integrating multiple therapeutic and imaging functions may find tremendous biomedical applications. However, the development of a simple yet potent theranostic nanosystem with a high payload and microenvironment responsiveness enhancing imaging‐guided cancer therapy is still a great challenge. Herein, a kind of MnCO‐entrapped mesoporous polydopamine nanoparticles are developed, which reach a 1.5 mg payload per gram carrier and exhibit marked theranostic capability through effective CO/Mn²⁺ generation and photothermal conversion inside the H⁺ and H₂O₂‐enriched tumor microenvironment, for a magnetic resonance/photoacoustic bimodal imaging‐guided tumor therapy. The multifunctional nanosystem exhibits a biocompatibility highly desirable for in vivo application and superior performance in inhibiting tumor growth and recurrence via combination CO and photothermal therapy.     

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.     

pH‐Responsive Cyanine‐Grafted Graphene Oxide for Fluorescence Resonance Energy Transfer‐Enhanced Photothermal Therapy

Stimuli‐responsive anticancer agents are of particular interest in the field of cancer therapy. Nevertheless, so far stimuli‐responsive photothermal agents have been explored with limited success for cancer photothermal therapy (PTT). In this work, as a proof‐of‐concept, a pH‐responsive photothermal nanoconjugate for enhanced PTT efficacy, in which graphene oxide (GO) with broad NIR absorbance and effective photothermal conversion efficiency is selected as a typical model receptor of fluorescence resonance energy transfer (FRET), and grafted cyanine dye (e.g., Cypate) acts as the donor of near‐infrared fluorescence (NIRF), is reported for the first time. The conjugate of Cypate‐grafted GO exhibits different conformations in aqueous solutions at various pH, which can trigger pH‐dependent FRET effect between GO and Cypate and thus induce pH‐responsive photothermal effect of GO‐Cypate. GO‐Cypate exhibits severe cell damage owing to the enhanced photothermal effect in lysosomes, and thus generate synergistic PTT efficacy with tumor ablation upon photoirradiation after a single‐dose intravenous injection. The photothermal nanoconjugate with broad NIR absorbance as the effective receptor of FRET can smartly convert emitted NIRF energy from donor cyanine dye into additional photothermal effect for improving PTT. These results suggest that the smart nanoconjugate can act as a promising stimuli‐responsive photothermal nanoplatform for cancer therapy.     

Dual‐Targeted Photopenetrative Delivery of Multiple Micelles/Hydrophobic Drugs by a Nanopea for Enhanced Tumor Therapy

A photoresponsive pea‐like capsule (nanopea) that also represents a photothermal agent is constructed by wrapping multiple polymer micelles (polyvinyl alcohol, PVA) in reduced graphene oxide nanoshells through a double emulsion approach. Resulting nanopeas can transport multiple PVA micelles containing the fully concealed hydrophobic drug docetaxel (DTX) which can be later released by a near‐infrared photoactuation trigger. Through integrating the rod‐shaped adhesion and lactoferrin (Lf) targeting, the nanopea enhances both uptake by cancer cellc in vitro and particle accumulation at tumor in vivo. A photopenetrative delivery of micelles/DTX to the tumor site is actuated by NIR irradiation which ruptures the nanopeas as well as releases nanosized micelles/DTX. This trigger also results in thermal damage to the tumor and increases the micelles/DTX permeability, facilitating drug penetration into the deep tumor far from blood vessels for thermal chemotherapy. This nanopea with the capability of imaging, enhanced tumor accumulation, NIR‐triggered tumor penetration, and hyperthermia ablation for photothermal chemotherapy boosts tumor treatment and shows potential for use in other biological applications.     

Long‐Circulating Drug‐Dye‐Based Micelles with Ultrahigh pH‐Sensitivity for Deep Tumor Penetration and Superior Chemo‐Photothermal Therapy

Nanocarriers for chemo‐photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug‐dye‐based micelle is designed by making the best of the structural features of small‐molecule drugs. P‐DOX is synthesized by conjugating doxorubicin (DOX) with poly(4‐formylphenyl methacrylate‐co‐2‐(diethylamino) ethyl methacrylate)‐b‐polyoligoethyleneglycol methacrylate (P(FPMA‐co‐DEA)‐b‐POEGMA) via imine linkage. Through the π–π stacking interaction, IR780, a near‐infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780‐PDMs) with the P‐DOX. The IR780‐PDMs show remarkably long blood circulation (t_1/2β = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780‐PDMs can dissociate into small‐size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep‐seated tumor cells. Owing to the high delivery efficiency and superior chemo‐photothermal therapeutic efficacy of IR780‐PDMs, 97.6% tumor growth in the A549 tumor‐bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg^?1; IR780, 0.8 mg kg^?1). This work presents a brand‐new strategy for long‐acting intensive cancer therapy.     

Self‐Assembly of Therapeutic Peptide into Stimuli‐Responsive Clustered Nanohybrids for Cancer‐Targeted Therapy

Clinical translation of therapeutic peptides, particularly those targeting intracellular protein–protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide–Au nanohybrid, followed by further self‐assembling into higher‐order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed β‐catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/β‐catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD‐L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide‐derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer.     

Self‐Mineralized Photothermal Bacteria Hybridizing with Mitochondria‐Targeted Metal–Organic Frameworks for Augmenting Photothermal Tumor Therapy

A photothermal bacterium (PTB) is reported for tumor‐targeted photothermal therapy (PTT) by using facultative anaerobic bacterium Shewanella oneidensis MR‐1 (S. oneidensis MR‐1) to biomineralize palladium nanoparticles (Pd NPs) on its surface without affecting bacterial activity. It is found that PTB possesses superior photothermal property in near infrared (NIR) regions, as well as preferential tumor‐targeting capacity. Zeolitic imidazole frameworks‐90 (ZIF‐90) encapsulating photosensitizer methylene blue (MB) are hybridized on the surface of living PTB to further enhance PTT efficacy. MB‐encapsulated ZIF‐90 (ZIF‐90/MB) can selectively release MB at mitochondria and cause mitochondrial dysfunction by producing singlet oxygen (¹O₂) under light illumination. Mitochondrial dysfunction further contributes to adenosine triphosphate (ATP) synthesis inhibition and heat shock proteins (HSPs) down‐regulated expression. The PTB‐based therapeutic platform of PTB@ZIF‐90/MB demonstrated here will find great potential to overcome the challenges of tumor targeting and tumor heat tolerance in PTT.     

Photoresponsive Protein–Graphene–Protein Hybrid Capsules with Dual Targeted Heat‐Triggered Drug Delivery Approach for Enhanced Tumor Therapy

A novel photo‐responsive protein–graphene–protein (PGP) capsule that doubles as a photothermal agent with core/shell structure is constructed by anchoring reduced graphene oxide nanosheets on one‐component protein (lactoferrin) shell through a double emulsion method. PGP capsules can transport fully concealed hydrophilic anticancer cargo, doxorubicin (Dox), with a large payload (9.43 μmol g^‐1) to be later unloaded in a burst‐like manner by photo‐actuation triggered by near‐infrared irradiation. Being biocompatible yet with a high cancer cell targeting efficiency, PGP capsules have successfully eradicated subcutaneous tumors in 10 d following a single 5 min NIR irradiation without distal damage. Besides, the photochemothermal therapy of PGP capsules eradicates tumor cells not only in the light‐treating area but also widely light‐omitted tumor cells, overcoming the tumor recurrence due to efficient cell killing efficacy. These results demonstrate that the PGP capsule is a potential new drug delivery platform for local‐targeting, on‐demand, photoresponsive, combined chemotherapy/hyperthermia for tumor treatment and other biomedical applications.