Dual-responsive nanoparticles targeting bone microenvironment for synergistic chemoimmunotherapy of osteosarcoma by remodeling immune microenvironment

Low delivery efficiency of chemotherapy drugs, poor immunogenicity and suppressive immune micro-environment of tumors seriously affect the prognosis of osteosarcoma (OS) patients. Although promising strategies concerning delivery approaches and immunotherapy have been proposed, few patients with OS could actually benefit from them. The reasons may be attributed to the low efficiency for passive accu-mulation, the deficiency in tumor immunogenicity, and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Here, we report dual-responsive (pH-responsive and glutathione [GSH]-responsive) nanoparticles (NP2), which possess a high affinity for bone minerals and tumors, to simultaneously enhance the anti-tumor efficacy and stimulate the immune response. Specifically, upon reaching the acidic tumor micro-environment (TME), NP2 released positively charged nanoparticles (NP1) and negatively charged zoledronic acid (ZA). NP1 exhibited powerful antitumor effects with the assistance of ZA and triggered strong im-munogenic cell death (ICD) effect, thereby promoting the maturation of dendritic cells (DCs) and infiltration of CTLs. Meanwhile, NP2 remodeled suppressive TME with the adjuvanticity of ZA, reducing myeloid-de-rived suppressor cells (MDSCs) and regulatory T cells (Tregs), and repolarizing tumor associated macro-phages (TAMs). At the same time, NP2 could increase programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, revealing excellent inhibitory effects for tumor growth with immune-checkpoint blockade (ICB) immunotherapy. To sum up, this study exemplified a rational design of bone-targeting na-noparticles to promote antitumor efficacy and immune response, thereby shedding light on the strategy of the combination of chemotherapy and immunotherapy as a potential clinical therapy for OS. (c) 2023 Published by Elsevier Ltd.

Automated summary

Dual-responsive nanoparticles (NP2) that can respond to pH and glutathione [GSH] enhance the delivery efficiency of chemotherapy drugs, stimulate the immune response, and remodel the tumor micro-environment, thereby improving the prognosis of osteosarcoma (OS) patients.