Nanozyme‐based tumor catalytic therapy has attracted widespread attention in recent years. However, its therapeutic outcomes are diminished by many factors in the tumor microenvironment (TME), such as insufficient endogenous hydrogen peroxide (H2O2) concentration, hypoxia, and immunosuppressive microenvironment. Herein, an immunomodulation‐enhanced nanozyme‐based tumor catalytic therapy strategy is first proposed to achieve the synergism between nanozymes and TME regulation. TGF‐β inhibitor (TI)‐loaded PEGylated iron manganese silicate nanoparticles (IMSN) (named as IMSN‐PEG‐TI) are constructed to trigger the therapeutic modality. The results show that IMSN nanozyme exhibits both intrinsic peroxidase‐like and catalase‐like activities under acidic TME, which can decompose H2O2 into hydroxyl radicals (•OH) and oxygen (O2), respectively. Besides, it is demonstrated that both IMSN and TI can regulate the tumor immune microenvironment, resulting in macrophage polarization from M2 to M1, and thus inducing the regeneration of H2O2, which can promote catalytic activities of IMSN nanozyme. The potent antitumor effect of IMSN‐PEG‐TI is proved by in vitro multicellular tumor spheroids (MCTS) and in vivo CT26‐tumor‐bearing mice models. It is believed that the immunomodulation‐enhanced nanozyme‐based tumor treatment strategy is a promising tool to kill cancer cells.

The highly immunosuppressive tumor microenvironment (TME) in solid tumors often dampens the efficacy of immunotherapy. In this study, bacterial outer membrane vesicles (OMVs) are demonstrated as powerful immunostimulants for TME reprogramming. To overcome the obstacles of antibody‐dependent clearance and high toxicity induced by OMVs upon intravenous injection (a classic clinically relevant delivery mode), calcium phosphate (CaP) shells are employed to cover the surface of OMVs, which enables potent OMV‐based TME reprograming without side effects. Meanwhile, the pH‐sensitive CaP shells facilitate the neutralization of acidic TME, leading to highly beneficial M2‐to‐M1 polarization of macrophages for improved antitumor effect. Moreover, the outer shells can be integrated with functional components like folic acid or photosensitizer agents, which facilitates the use of the OMV‐based platform in combination therapies for a synergic therapeutic effect.

Macrophage-tumor chimeric exosomes inhibit tumor growth in multiple mouse models by stimulating the immune response and tumor microenvironment.

Glioblastoma multiforme (GBM) is an aggressive brain cancer with a poor prognosis and few treatment options. Here, building on the observation of elevated lactate (LA) in resected GBM, we develop biomimetic therapeutic nanoparticles (NPs) that deliver agents for LA metabolism-based synergistic therapy. Because our self-assembling NPs are encapsulated in membranes derived from glioma cells, they readily penetrate the blood-brain barrier and target GBM through homotypic recognition. After reaching the tumors, lactate oxidase in the NPs converts LA into pyruvic acid (PA) and hydrogen peroxide (H2O2). The PA inhibits cancer cell growth by blocking histones expression and inducing cell-cycle arrest. In parallel, the H2O2 reacts with the delivered bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate to release energy, which is used by the co-delivered photosensitizer chlorin e6 for the generation of cytotoxic singlet oxygen to kill glioma cells. Such a synergism ensures strong therapeutic effects against both glioma cell-line derived and patient-derived xenograft models.

The poor understanding of the complex multistep process taken by nanocarriers during the delivery process limits the delivery efficiencies and further hinders the translation of these systems into medicine. Here, we describe a series of six self-assembled nanocarrier types with systematically altered physical properties including size, shape, and rigidity, as well as both in vitro and in vivo analyses of their performance in blood circulation, tumor penetration, cancer cell uptake, and anticancer efficacy. We also developed both data and simulation-based models for understanding the influence of physical properties, both individually and considered together, on each delivery step and overall delivery process. Thus, beyond finding that nanocarriers that are simultaneously endowed with tubular shape, short length, and low rigidity outperformed the other types, we now have a suit of theoretical models that can predict how nanocarrier properties will individually and collectively perform in the multistep delivery of anticancer therapies.