Reshaped\nLocal and Systemic Immune Responses Triggered\nby a Biomimetic Multifunctional Nanoplatform Coordinating Multi-Pathways\nfor Cancer Therapy

Immunotherapy\nhas fundamentally transformed the clinical cancer\ntreatment landscape; however, achieving intricate and multifaceted\nmodulation of the immune systems remains challenging. Here, a multipathway\ncoordination of immunogenic cell death (ICD), autophagy, and indoleamine\n2,3-dioxygenase-1 (IDO1) was achieved by a biomimetic nano-immunomodulator\nassembled from a chemotherapeutic agent (doxorubicin, DOX), small\ninterfering RNA (siRNA) molecules targeting IDO1 (siIDO1), and the\nzeolitic imidazolate framework-8 (ZIF-8). After being camouflaged\nwith a macrophage membrane, the biomimetic nanosystem, named mRDZ,\nenriched in tumors, which allowed synergistic actions of its components\nwithin tumor cells. The chemotherapeutic intervention led to a compensatory\nupregulation in the expression of IDO1, consequently exerting an inhibitory\neffect on the reactive oxygen species (ROS) and autophagic responses\ntriggered by DOX and ZIF-8. Precise gene silencing of IDO1 by siIDO1\nalleviated its suppressive influence, thereby facilitating increased\nROS production and improved autophagy, ultimately bolstering tumor\nimmunogenicity. mRDZ exhibited strong capability to boost potent local\nand systemic antitumor immune responses with a feature of memory,\nwhich led to the effective suppression of the growth, lung metastasis,\nand recurrence of the tumor. Serving as an exemplary model for the\nstraightforward and potent reshaping of the immune system against\ntumors, mRDZ offers valuable insights into the development of immunomodulatory\nnanomaterials for cancer therapy.