Targeting USP7 - a nano-therapeutic approach to restore and reactivate P53 for promoting apoptosis in glioma therapy

BACKGROUND: Glioblastoma remains one of the most lethal brain malignancies due to its profound molecular heterogeneity, invasive biology, and poor drug penetration across the BBB. Clinically, USP7 is highly overexpressed and contributes to tumor aggressiveness in glioma. METHODS: Native USP7 inhibitors (P22077 and P5091) exhibit potent cytotoxicity but suffer from poor solubility, suboptimal pharmacokinetics, and limited BBB permeability, restricting their translational potential. To overcome these limitations, we developed PLGA-based nanoparticles of both inhibitors (nP22077 and nP5091) and observed efficient encapsulation with better pharmacokinetic profiles. RESULTS: assays. In subcutaneous xenografts and a stringent stereotactic orthotopic glioma model, nP5091 achieved substantial tumor regression, minimal systemic toxicity, and significantly prolonged survival, supported by strong molecular evidence of P53 reactivation and apoptotic signaling. CONCLUSION: Collectively, this work establishes nano-enabled delivery of USP7 inhibitors as a robust, mechanistically driven therapeutic strategy capable of overcoming key pharmacological barriers and offering a promising avenue for future glioma treatment.