Search

Abstract Photodynamic immunotherapy which combines photodynamic therapy with immunotherapy has become an important and effective method for the treatment of cancer. However, most cancer photodynamic immunotherapeutic systems are not able to achieve precise release of immunomodulators, resulting in systemic side effects and poor patient outcomes. Herein, a dual‐activatable nano‐immunomodulator (DIR NP), which both its photodynamic effect and agonist release can be activated under specific stimuli, is reported for precision cancer photodynamic immunotherapy. The DIR NP is self‐assembled from an R848‐conjugated amphiphilic polymer (mPEG‐TK‐R848) and a hydrophobic oxidized bovine serum albumin (BSA‐SOH)‐conjugatable photosensitizer (DIR). DIR NPs may generate a small amount of 1O2 under 808 nm laser irradiation, leading to the cleavage of thioketal (TK) moiety and release of R848 and DIR. The released DIR may conjugate with tumor‐overexpressed BSA‐SOH, improving its photodynamic efficiency and NIR‐II fluorescence signal. Such photodynamic efficiency improvement may further enhance the release of cargoes upon irradiation. The activated photodynamic effect induces immunogenic cell death (ICD) to release immune factors and R848 can enhance the maturation of dendritic cells for inhibiting the growth of both primary and distant tumors and eliminating lung metastasis. Therefore, this study provides a dual‐activatable intelligent nano‐immunomodulator for precise regulation of tumor photodynamic immunotherapy.

Abstract Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion‐induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)‐ and RAGE (receptor for advanced glycation end products)‐ comodified macrophage membrane‐coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9‐siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia‐reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane‐coated nanoparticles may represent a new therapeutic intervention for MIRI.

Abstract Chimeric antigen receptor (CAR)‐T cell therapy is a transformative treatment against advanced malignancies. Unfortunately, once administrated in vivo, CAR‐T cells become out of artificial control, and fierce response to CAR‐T therapy may cause severe adverse events, represented by cytokine‐release syndrome and on‐target/off‐tumor effects. Here, a nanomodified switch strategy is developed, leading to sustained and precise “on‐tumor only” activation of CAR‐T cells. Here, original gelatinase‐responsive nanoparticles (NPs) are used to selectively deliver the heterodimerizing switch, which is the key component of switchable CAR with separated activation modules. The “NanoSwitch” is tumor‐specific, thus inactivated switchable CAR‐T cells do little harm to normal cells, even if the normal cells express the target of CAR‐T. Owing to the sustained‐release effect of NPs, the CAR‐T cells are activated smoothly, avoiding sudden release of cytokine. These data introduce NanoSwitch as a universal and applicable solution to safety problems of CAR‐T therapy regardless of the target.