Injectable Trojan Horse Hydrogel Unleashing Penetrable and Immunostimulatory Nanomicelles for Postoperative Treatment of Glioblastoma

Glioblastoma multiforme (GBM) remains almost universally fatal due to its aggressive recurrence after surgical resection, driven by residual infiltrative cells and a profoundly immunosuppressive microenvironment. Capitalizing on the intrinsic lubricating feature of Pluronic F127 (PF127), here, we engineered an injectable, dual-cross-linked hydrogel that enabled the in situ generation of highly penetrable and immunostimulatory nanomicelles to combat GBM relapse. The hydrogel (PF127-PTX Gel) was constructed by physical and chemical cross-linking paclitaxel-conjugated PF127 (PF127-PTX) with amino- and aldehyde-functional PF127 polymers. The dual-cross-linking significantly prolonged the local retention of PF127-PTX Gel in comparison with native PF-127 hydrogel. Upon degradation, PF127-PTX Gel released small PF127-PTX nanomicelles to markedly enhance the penetration and diffusion through brain tissue. Beyond direct tumor cells cytotoxicity, the released nanomicelles reprogramed the immunosuppressive macrophages and restored their phagocytic functions, thus alleviating the postoperative immunosuppressive microenvironment. In orthotopic GBM resection models, treatment with PF127-PTX alone achieved 50% mice survived over 100 days after tumor inoculation, and its combination with anti-CD47 antibody further raised the long-term survival rate to 66.7%. This innovative strategy presents a potent approach for preventing postoperative GBM recurrence through localized, combinatorial chemoimmunotherapy.