The engineering of a series of multienzyme‐mimicking covalent organic frameworks (COFs), COF‐909‐Cu, COF‐909‐Fe, and COF‐909‐Ni, as pyroptosis inducers, remodeling the tumor microenvironment to boost ...cancer immunotherapy, is reported. Mechanistic studies reveal that these COFs can serve as hydrogen peroxide (H2O2) homeostasis disruptors to elevate intracellular H2O2 levels, and they not only exhibit excellent superoxide dismutase (SOD)‐mimicking activity and convert superoxide radicals (O2•−) to H2O2 to facilitate H2O2 generation, but also possess outstanding glutathione peroxidase (GPx)‐mimicking activity and deplete glutathione (GSH) to alleviate the scavenging of H2O2. Meanwhile, the outstanding photothermal therapy properties of these COFs can accelerate the Fenton‐like ionization process to facilitate their chemodynamic therapy efficiency. One member, COF‐909‐Cu, can robustly induce gasdermin E (GSDME)‐dependent pyroptosis and remodel the tumor microenvironment to trigger durable antitumor immunity, thus promoting the response rate of αPD‐1 checkpoint blockade and successfully restraining tumor metastasis and recurrence.
A series of multienzyme‐mimicking covalent organic frameworks (COFs) is constructed by dispersing active sites into the COF backbone. In contrast to their corresponding bulk species, these enzyme‐mimicking COFs can serve as H2O2 homeostasis disruptors to elevate intracellular H2O2 levels, thus exhibiting excellent chemodynamic therapy and pyroptosis efficacy, favorable for boosting cancer immunotherapy.
Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha ...(SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.
Radiotherapy is an important therapeutic strategy for cancer treatment through direct damage to cancer cells and augmentation of antitumor immune responses. However, the efficacy of radiotherapy is ...limited by hypoxia-mediated radioresistance and immunosuppression in tumor microenvironment. Here, we construct a stabilized theranostic nanoprobe based on quantum dots emitting in the near-infrared IIb (NIR-IIb, 1,500-1,700 nm) window modified by catalase, arginine-glycine-aspartate peptides and poly(ethylene glycol). We demonstrate that the nanoprobes effectively aggregate in the tumor site to locate the tumor region, thereby realizing precision radiotherapy with few side-effects. In addition, nanoprobes relieve intratumoral hypoxia and reduce the tumor infiltration of immunosuppressive cells. Moreover, the nanoprobes promote the immunogenic cell death of cancer cells to trigger the activation of dendritic cells and enhance T cell-mediated antitumor immunity to inhibit tumor metastasis. Collectively, the nanoprobe-mediated immunogenic radiotherapy can boost the abscopal effect to inhibit tumor metastasis and prolong survival.
For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have ...reported a phenomenon known as “accelerated blood clearance (ABC)” where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane‐coated Fe3O4 nanoparticles (Fe3O4@RBC NPs) rely on CD47, which is a “don't eat me” marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein‐alpha (SIRP‐α) receptor. Fe3O4@RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe3O4@RBC NPs does not elicit immune responses on neither the cellular level (myeloid‐derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane‐camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long‐existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.
Red blood cell membrane‐camouflaged Fe3O4 nanoparticles (Fe3O4@RBC NPs) exhibit prolonged circulation time in the blood with no adverse effects. There is little change between a first and second dose, and no accelerated blood clearance is seen, as is generally the case for PEGylated nanomaterials. This is a significant advancement toward developing biomaterials that are able to resist both immune response and rapid clearance.
Overcoming innate or adaptive resistance to immune checkpoint inhibitor therapy in solid tumors with limited T‐cell responses remains challenging. Increasing evidence has indicated that epigenetic ...alterations, especially overexpression of DNA methyltransferase and immunosuppressive adenosine, are major obstacles to T cell activation. Here, a tumor microenvironment (TME) inspired prodrug nanomicelle (AOZN) composed of the epigenetic modulator γ‐oryzanol (Orz), the adenosine inhibitor α, β‐methylene adenosine 5′ diphosphate (AMPCP), and GSH‐activable crosslinker, is rationally designed. High glutathione redox triggers Orz and AMPCP release in the TME. The released Orz act as a DNA methyltransferases inhibitor to upregulate gasdermin D (GSDMD) expression and AMPCP converted procaspase‐1 into active caspase‐1 by increasing ATP levels. Active caspase‐1 elicited GSDMD cleavage and induced pyroptosis in tumor cells. Furthermore, it is demonstrated that Orz and AMPCP likely have a synergistic effect in combating the immunosuppressive TME. Moreover, Orz enhances programmed death‐ligand 1 (PD‐L1) expression and sensitize tumors to anti‐PD‐L1 therapy. Thus, the AOZNs nano‐formulation drastically improves the hydrophobic properties of Orz with advantages of safe, affordable, readily available, and efficiency in regressing tumor growth, enhancing PD‐L1 responsive rate and prolonging survival of the B16F10 melanoma‐bearing mouse model. As a result, AOZNs provides a promising strategy for enhancing cancer immunotherapy.
A GSH‐activable prodrug nanomicelle that can deliver natural epigenetic agent γ‐oryzanol and adenosine inhibitor AMPCP to the tumor for potentiating cancer immunotherapy is developed. The prodrug nanomicelle can enhance immunogenicity and immunogenic pyroptosis in tumor cells and reverses the immuosuppresive tumor microenvironment.
Immunotherapy is one of the most promising clinical modalities for the treatment of malignant tumors and has shown excellent therapeutic outcomes in clinical settings. However, it continues to face ...several challenges, including long treatment cycles, high costs, immune‐related adverse events, and low response rates. Thus, it is critical to predict the response rate to immunotherapy by using imaging technology in the preoperative and intraoperative. Here, the latest advances in nanosystem‐based biomaterials used for predicting responses to immunotherapy via the imaging of immune cells and signaling molecules in the immune microenvironment are comprehensively summarized. Several imaging methods, such as fluorescence imaging, magnetic resonance imaging, positron emission tomography imaging, ultrasound imaging, and photoacoustic imaging, used in immune predictive imaging, are discussed to show the potential of nanosystems for distinguishing immunotherapy responders from nonresponders. Nanosystem‐based biomaterials aided by various imaging technologies are expected to enable the effective prediction and diagnosis in cases of tumors, inflammation, and other public diseases.
The predicting process of immunotherapy utilizing imaging technology holds huge promise in boosting the response rate of clinical patients. Here, the latest progress in imaging‐guided nanosystem‐based biomaterials for real‐time monitoring of immune cells and immune signaling molecules is summarized to predict the efficacy of immunotherapy, and future directions and main challenges for the visualization of response rates are also discussed.
A major challenge for traditional cancer therapy, including surgical resection, chemoradiotherapy, and immunotherapy, is how to induce tumor cell death and leverage the host immune system at the same ...time. Here, a myeloid‐derived suppressor cell (MDSC) membrane‐coated iron oxide magnetic nanoparticle (MNP@MDSC) to overcome this conundrum for cancer therapy is developed. In this study, MNP@MDSC demonstrates its superior performance in immune evasion, active tumor‐targeting, magnetic resonance imaging, and photothermal therapy (PTT)‐induced tumor killing. Compared with red blood cell membrane‐coated nanoparticles (MNPs@RBC) or naked MNPs, MNP@MDSCs are much more effective in active tumor‐targeting, a beneficial property afforded by coating MNP with membranes from naturally occurring MDSC, thus converting the MNP into “smart” agents that like to accumulate in tumors as the source MDSCs. Once targeted to the tumor microenvironment, MNPs@MDSC can act as a PTT agents for enhanced antitumor response by inducing immunogenic cell death, reprogramming the tumor infiltrating macrophages, and reducing the tumor's metabolic activity. These benefits, in combination with the excellent biocompatibility and pharmacological kinetics characteristics, make MNP@MDSC a promising, multimodal agent for cancer theranostics.
Myeloid‐derived suppressor cell (MDSC) membranes are collected from tumor‐bearing mice and further used for magnetic Fe3O4 nanoparticle (MNP) coating. The resulting MDSC‐mimicking nanoparticles (MNP@MDSC) demonstrate superior performance in immune evasion, active tumor‐targeting, magnetic resonance imaging, photothermal therapy‐induced tumor killing, and excellent biocompatibility and pharmacological kinetics characteristics. These benefits make MNP@MDSC a promising, multimodal agent for cancer theranostics.
Chiral 1,2‐amino alcohols are widely represented in biologically active compounds from neurotransmitters to antivirals. While many synthetic methods have been developed for accessing amino alcohols, ...the direct aminohydroxylation of alkenes to unprotected, enantioenriched amino alcohols remains a challenge. Using directed evolution, we have engineered a hemoprotein biocatalyst based on a thermostable cytochrome c that directly transforms alkenes to amino alcohols with high enantioselectivity (up to 2500 TTN and 90 % ee) under anaerobic conditions with O‐pivaloylhydroxylamine as an aminating reagent. The reaction is proposed to proceed via a reactive iron‐nitrogen species generated in the enzyme active site, enabling tuning of the catalyst's activity and selectivity by protein engineering.
Go direct: A hemoprotein catalyst was engineered to transform alkenes directly to amino alcohols with high enantioselectivity. Derived by directed evolution from a thermostable cytochrome c, the protein catalyst uses O‐pivaloylhydroxylamine to generate a reactive iron‐nitrogen species.
Cancer cell membrane‐coated upconversion nanoprobes (CC‐UCNPs) with immune escape and homologous targeting capabilities are used for highly specific tumor imaging. The combination of UCNPs with ...biomimetic cancer cell membranes embodies a novel materials design strategy and presents a compelling class of advanced materials.
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