TAM-preferential nanoparticles intracellularly self-assembled for enhanced macrophage repolarization and cancer immunotherapy

Immunomodulatory therapy by re-educating M2-like tumor-associated macrophage (TAM) is often clinically impeded due to the lack of a coordinated platform to sustainably restrain the immunosuppressive tumor microenvironment (ITM). TAM repolarization efficiency is relatively low, with the limited internalization and intracellular retention of repolarizing agents, given the high plasticity of macrophages reacting to the complicated tumor microenvironment. Herein, a versatile nanoplatform is developed, where M2 macrophage binding peptide (M2pep)-modified gelatin (GM), acting as a TAM-targeting shell, is grafted onto hollow copper sulfide nanoparticles respectively modified with β-cyclodextrin (CD) and adamantane (Ada), and M1-inducing imiquimod (IMD) is encapsulated into inner cores. We showed the preferential internalization of this nanomedicine into TAMs both in vivo and in vitro. In addition, the formation of intracellular supramolecular aggregates could lead to a long retention time in TAMs. Combination of the nanomedicine with anti-cytotoxic T-lymphocyte antigen-4 (αCTLA4) resulted in retarded tumor growth, prolonged overall survival and improved immunotherapeutic response. Overall, this nanoplatform offers a coordinated strategy that allows preferential recognition and internalization by TAM and sustainable intracellular drug release, leading to efficient reversal of ITM and highly effective T cell-mediated immunotherapy.