A siRNA-Assisted Assembly Strategy to Simultaneously Suppress “Self” and Upregulate “Eat-Me” Signals for Nanoenabled Chemo-Immunotherapy

Effectively activating macrophages that can engulf cancer cells is a promising immunotherapeutic strategy but remains a major challenge due to the expression of "self" signals (e.g., CD47 molecules) by tumor cells to prevent phagocytosis. Herein, we explored a siRNA-assisted assembly strategy for the simultaneous delivery of siRNA and mitoxantrone hydrochloride (MTO·2HCl) via PLGA-based nanoparticles. The siRNA suppressed a "self" signal by silencing the CD47 gene, while the MTO induced surface exposure of calreticulin (CRT) to provide an "eat-me" signal. The siRNA-assisted assembly strategy synergistically increased the phagocytosis of tumor cells by macrophages, promoted effective antigen presentation, and initiated T cell-mediated immune responses in two aggressive tumor animal models of melanoma and colon cancer, eventually achieving significantly improved antitumor activity. This study provides a straightforward codelivery strategy to simultaneously suppress "self" and upregulate "eat-me" signals to potentiate macrophage-mediated immunotherapy.