TME-responsive nanocomposite hydrogel with targeted capacity for enhanced synergistic chemoimmunotherapy of MYC-amplified osteosarcoma

The oncogene MYC is one of the most commonly activated oncogenic proteins in human tumors, with nearly one-fourth of osteosarcoma showing MYC amplification and exhibiting the worst clinical outcomes. The clinical efficacy of single radiotherapy, chemotherapy, and immunotherapy for such osteosarcoma is poor, and the dysregulation of MYC amplification and immune-suppressive tumor microenvironment (TME) may be potential causes of anti-tumor failure. To address the above issues, we developed an injectable TME-responsive nanocomposite hydrogel to simultaneously deliver an effective MYC inhibitor (NHWD-870) and IL11Rα-targeted liposomes containing cisplatin-loaded MnO 2 (Cis/Mn@Lipo-IL11). After in situ administration, NHWD-870 effectively degrades MYC and downregulates CCL2 and IL13 cytokines to trigger M1 type activation of macrophages. Meanwhile, targeted delivery of Cis/Mn@Lipo-IL11 reacts with excess intratumoral GSH to generate Mn 2+ and thus inducing excess active oxygen species (ROS) production through Fenton-like reaction, along with cisplatin, thereby inducing immunogenic cell death (ICD) to promote dendritic cell maturation. Through synergistic regulation of MYC and ICD levels, the immune microenvironment was reshaped to enhance immune infiltration. In the osteosarcoma-bearing model, the nanocomposite hydrogel significantly enhanced tumor T cell infiltration, induced effective anti-tumor immunity and attenuated lung metastasis. Therefore, our results reveal a powerful strategy for targeted combination therapy of MYC-amplified osteosarcoma. We have developed an injectable TME-responsive nanocomposite hydrogel loaded with an effective MYC inhibitor NHWD-870 and IL11Ra-targeted liposomes containing cisplatin-loaded MnO 2 , establishing a targeted chemotherapy-chemodynamic therapy-immunotherapy triple-combination therapy to restrain cancer growth. By regulating the levels of MYC and ICD, the proportion of M1 macrophages and mature dendritic cells were enhanced and thereby strengthening anti-tumor immunity to inhibit MYC-amplified osteosarcoma growth and metastasis. • An injectable TME-responsive nanocomposite hydrogel was developed for targeted delivery of MYC inhibitor and cisplatin. • TEM-responsive nanocomposite hydrogel was able to control MYC and ICD levels for the treatment of MYC-amplified osteosarcoma. • An effective therapeutic strategy was presented for targeted therapy of MYC-amplified osteosarcoma growth and metastasis.