Hyaluronate-Based Self-Stabilized Nanoparticles for Immunosuppression Reversion and Immunochemotherapy in Osteosarcoma Treatment

Immunotherapy is regarded as a potential strategy to combat cancer, especially when immunotherapy is combined with appropriate chemotherapy. However, the immunosuppressive tumor microenvironment (TME) and serious side effects extremely limit the application of immunotherapy. Herein, a self-stabilized hyaluronic acid nanoparticle is synthesized for tumor-targeted delivery of doxorubicin (DOX), cisplatin (CDDP), and resiquimod (R848) in osteosarcoma immunochemotherapy, which is referred to as ^CDDPNP_DOX&R848. ^CDDPNP_DOX&R848 exhibits sufficient stability, great pH responsibility, and brilliant tumor-targeting accumulation in vivo, which make it suitable for further in vivo applications. After intravenous injection, ^CDDPNP_DOX&R848 can release the loaded cargoes under the acidic TME continuously. DOX can induce tumor cell apoptosis in combination with CDDP and trigger immunogenic cell death. More importantly, the immune-activated TME created by R848 can facilitate tumor-associated antigen presentation and antitumor immunity elicitation. Benefiting from the synergistic effect of chemotherapy and immunotherapy, the growth of tumors and lung metastasis was greatly inhibited by ^CDDPNP_DOX&R848 in the K7M2 orthotopic osteosarcoma mouse model. Thus, this intelligent codelivery platform might be a competitive candidate for osteosarcoma immunochemotherapy.