Dual‐Responsive Immunomodulatory RNAi Nanoplatform for Effective Immune Checkpoint Blockade and Enhanced Cancer Immunotherapy

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Abstract Immune checkpoint blockade (ICB) therapy has become the first‐line treatment for cancer patients. However, the low response rate remains a clinical pain‐point. Anti‐hyperglycemic drug metformin has shown remarkable anticancer effect with the unique characteristic of modulating tumor immune microenvironment (TIME). Therefore, combining ICB with metformin could be a promising strategy for enhanced cancer immunotherapy, which however remains challenged due to the low bioavailability and severe adverse effects of metformin. This work herein designs an amphiphilic reduction‐responsive metformin prodrug, which could complex small interfering RNA (siRNA) and then co‐assemble with an endosomal pH‐responsive PEGylated polymer to form a dual‐responsive immunomodulatory RNAi nanoplatform. Using the orthotopic and metastatic breast cancer (BCa) tumor models, this work demonstrates that this RNAi nanoplatform could silence PD‐L1 expression on BCa cells and suppress their proliferation via activating AMP‐activated protein kinase (AMPK). Moreover, this AMPK activation could suppress the secretion of tumor‐derived transforming growth factor β (TGF‐β) and interleukin 6 (IL‐6), which could enhance the maturation of dendritic cells (DCs) and activation of CD8 + T cells and impair the tumor infiltration of regulatory T cells (Tregs), myeloid‐derived suppressor cells (MDSCs), and tumor‐associated macrophages (TAMs), ultimately achieving the goal of enhanced cancer immunotherapy and significant inhibition of BCa tumor growth.

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