Journal
ACS NANO
Volume 15, Issue 10, Pages 16030-16042Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c04458
Keywords
siRNA-assisted assembly strategy; macrophage phagocytosis; CD47-SIRP alpha signaling; CRT exposure; immunotherapy
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Funding
- National Key R&D Program of China [2017YFA0205600]
- National Natural Science Foundation of China [51773067, 51822302, 52173121]
- Program for Guangdong Introducing innovative and Enterpreneurial Teams [2017ZT07S054]
- Natural Science Foundation for Distinguished Young Scholars of Guangdong Province [2017B030306002]
- High-level Hospital Construction Project [DFJH201905]
- Fundamental Research Funds for the Central Universities
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The study utilized a siRNA-assisted assembly strategy to deliver siRNA and MTO simultaneously, effectively enhancing phagocytosis of tumor cells by macrophages. This approach promoted antigen presentation and triggered T cell-mediated immune responses, leading to significantly improved antitumor activity in aggressive tumor animal models.
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 center dot 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.
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