Injectable and sprayable supramolecular prodrug hydrogel for long-acting chemo-hormonal therapy of prostate cancer

Postoperative biochemical recurrence and local tumor relapse remain major clinical challenges in managing prostate cancer. Here, we report an injectable and sprayable supramolecular paclitaxel prodrug nanofiber (PF) co-loaded with a potent androgen receptor inhibitor darolutamide (ODM) for long-acting chemo-hormonal therapy against prostate cancer. Upon spraying, ODM/PF rapidly undergoes in situ gelation, forming a uniform hydrogel depot that coats irregular surgical surfaces and enables sustained, controlled drug release in response to the reductive tumor microenvironment. This dual-acting chemo-hormonal strategy produces potent therapeutic synergy by combining paclitaxel-induced mitotic arrest and apoptosis with suppression of androgen receptor signaling. In a murine model of incomplete tumor resection, postoperative spraying of ODM/PF effectively prevented local recurrence, significantly outperforming either agent alone while maintaining a favorable systemic safety profile. Our findings establish ODM/PF as an immediate postoperative adjuvant platform that maximizes local drug concentrations, minimizes systemic exposure, and enables early control of potential residual disease, thereby substantially reducing the likelihood of tumor recurrence.