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 microenvironment 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 accumulation, 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 antitumor efficacy and stimulate the immune response. Specifically, upon reaching the acidic tumor microenvironment (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 immunogenic 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-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and repolarizing tumor associated macrophages (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 nanoparticles 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.