Dual PLGA nanoparticles co-encapsulating P5091 and Resveratrol synergistically target the USP7-MDM2-P53 axis for glioma therapy.

Abstract

Glioma, a Grade-IV brain tumor, often exhibits functional suppression of P53 signaling due to aberrant stabilization of MDM2 by the deubiquitinase USP7, presenting a therapeutically exploitable vulnerability that remains under-utilised because of poor drug bioavailability and limited blood-brain barrier penetration. Here, we developed a rationally designed PLGA-based dual-loaded nanoformulation co-encapsulating USP7 inhibitor P5091 and P53-modulating polyphenol Resveratrol, to significantly attenuate the USP7-MDM2-P53 axis. Guided by synergy analysis, nanoparticles were formulated at an optimized molar ratio enabling controlled and sustained drug release with favourable physicochemical stability. Dual nanoencapsulation significantly enhanced synergistic cytotoxicity in glioma cells and 3D spheroids by inducing apoptosis through significant P53 restoration. Dual co-encapsulation improves pharmacokinetics and suppresses tumor growth with improved survival in orthotopic glioma model without any obvious vital organs histological damage. These findings highlight a mechanism-guided nanotherapeutic strategy for glioma treatment.