A pH transformable nanocarrier for gradual and precise delivery of a natural immunomodulator and chemotherapy agent to trigger tumor apoptosis

Chemotherapy coupled with immunotherapy exerts strong antitumor effects. Research efforts have been directed to investigate the simultaneous delivery of immunomodulators and chemotherapeutic agents into immune or tumor cells. However, the optimal combination effects are undermined. In this study, we constructed a pH-hypersensitive multifunctional nano-platform (Dual NP) combining the procedural release and precise delivery of the natural immunomodulator, chlorogenic acid (CHA), and the chemotherapeutic agent, paclitaxel (PTX), to M2-TAMs and tumor cells, respectively. This combination is designed to increase the antitumor efficacy of PTX and increase the immunomodulatory effect of CHA to generate a potent immune response. We also assessed the in vitro and in vivo characteristics of Dual NP in repairing the immunosuppressive tumor microenvironment (TME) and exerting antitumor effects. Our findings indicated that targeted delivery and reversal of M2-TAMs by CHA can achieve a positive feedback loop on remodeling the immunosuppressive TME, such as increasing the infiltration of T cells and DCs, decreasing the proportion of MDSCs, elevating the levels of pro-inflammatory cytokines (IFN-γ, IL-2, and IL-12), and decreasing the levels of anti-inflammatory cytokines (IL-10 and TGF-β1). These findings show that intravenously administered Dual NP can be a potential treatment strategy for chemo-immunotherapy.