Manganese-coordinated liposome composite hydrogel for postoperative osteosarcoma recurrence prevention via press-accelerator/release-brake strategy

Mn-coordinated liposomes (AC@MLip-IL11) promote cellular uptake and lysosomal escape. • Mn 2+ and ADU-S100 activate STING, celastrol relieves AKT-mediated inhibition. • AC@MLip-IL11 induces ICD and activates STING, triggering antitumor immune responses. • AC@MLip-IL11 Gel effectively inhibits subcutaneous post-operative recurrence of OS. Surgical resection remains the standard treatment regimen for osteosarcoma (OS). However, residual tumor cells and postoperative immunosuppression frequently induce tumor recurrence and metastasis. Although STING agonist-based immunotherapy offers a promising strategy for postoperative treatment, its efficacy is limited by a narrow therapeutic window, susceptibility to enzymatic degradation, and negative regulatory mechanisms. To address these challenges, this study developed a manganese (Mn)-coordinated liposome (ADU-S100/celastrol@MnLip-IL11, AC@MLip-IL11) composite hydrogel to enhance local immunotherapeutic efficacy for post-resection OS. The core design of this system encompasses three aspects: (1) drug reservoir, whereby the hydrogel achieves sustained release, enabling prolonged therapeutic efficacy; (2) potent activation, as AC@MLip-IL11 promotes efficient cellular uptake and lysosomal escape, while Mn 2+ acts synergistically with ADU-S100 to “press the accelerator” for STING pathway activation; and (3) synergistic potentiation, whereby celastrol not only induces mitochondrial damage but also “releases the brake” on STING signaling by blocking AKT-mediated negative regulation. This “press-accelerator, release-brake” synergistic strategy promotes tumor apoptosis, triggers efficient STING signaling, promotes abundant type I interferon secretion, facilitates dendritic cell maturation, and elicits CD8 + T cell-mediated antitumor immune responses, demonstrating significant therapeutic efficacy in preventing tumor recurrence in a subcutaneous postoperative OS mouse model. In summary, this study provides a versatile engineered platform for the development of cancer immunotherapies and offers new intervention insights for postoperative tumor treatment. Download: Download high-res image (199KB) Download: Download full-size image