In Situ Formed Nanocomposite Hydrogel Improve Local Delivery of Antiangiogenic Agents and Immune Checkpoint Inhibitor for Cervical Carcinoma Therapy.

Abstract

Immune checkpoint blockade targeting the programmed cell death protein-1 (PD-1)/ligand (PD-L1) axis has emerged as a promising therapeutic strategy for cervical carcinoma. However, its clinical application remains limited by the immunosuppressive tumor microenvironment (TME) and poor targeting efficiency, particularly in solid tumors. To address these challenges, a nanocomposite hydrogel system (Apa/BPNPs@Gel) is developed by encapsulating PD-L1 inhibitor BMS202 nanoparticles coated with polyvinyl alcohol (BPNPs) into a polyvinyl alcohol/alginate hybrid hydrogel. This in situ formed hydrogel exhibits favorable biocompatibility and reactive oxygen species-dependent sequential drug release. Initially, the antiangiogenic agent apatinib (Apa) is released to alleviate tumor hypoxia through vascular normalization and enhance PD-L1 suppression, priming the TME for subsequent anti-PD(L)1 therapy. The hydrogel framework extends the residence time of BMS202 (a skeleton component), improving therapeutic efficacy. Notably, in preclinical cervical carcinoma models, Apa/BPNPs@Gel mediated combination therapy significantly inhibited tumor growth and prolonged survival by activating tumor-suppressed CD8+ T cells. Hence, this locally administrable hydrogel offers a versatile platform to modulate the immunosuppressive TME and enhance immunotherapeutic outcomes.