Hydrogel-Mediated Jamming of Exosome Communications That Counter Tumor Adaption in the Tumor Immune Microenvironment

Hypoxia, a common occurrence within solid tumors, can stimulate the dissemination of deceptive tumor exosomes, which function as communicative bridges and orchestrate the recruitment of various supportive cell types for enhanced tumor adaptability in a tumor immune microenvironment. Current nanotechnology provides us intelligent strategies to combat the hypoxic tumor microenvironment. However, once exposed to external stimuli, such as chemotherapy, tumor cells simultaneously release malignant signals to develop tumor migration and immunosuppression, posing challenges to clinical practice. Taking advantage of the membrane-targeting therapeutic strategy, the application of a self-assembled short peptide (PepABS-_py), affording hydrogels on tumor cell surfaces, can block exosome dissemination with fiber-like nanostructures and effectively limit the systemic adverse effects of traditional therapeutics. Moreover, PepABS-_py can attenuate the hypoxic tumor microenvironment in vivo by carrying an inhibitor of the hypoxic tumor-overexpressed CA IX enzyme, where hypoxia is also a crucial regulator to induce tumor exosomes and mediate intercellular communications within the immune system. Herein, its application on jamming exosome communications can target the T cell-related signaling pathway by regulating microRNAs in exosome cargoes and ultimately enhances CD8⁺ T cell infiltration and alleviates inflammatory monocytes at metastasis sites. Collectively, with the capability of blocking exosome dissemination, PepABS-_py can be applied as a promising tumor membrane-targeting therapeutic tool to counter tumor adaption within an immune microenvironment and further advance traditional chemotherapy.