EGFR-Degrading PROTACs and Calcium Peroxide Co-loaded Liposomes: Enabling EGFR Degradation and Hypoxia Alleviation as Dual Safeguards for NSCLC Therapy.

Proteolysis targeting chimeras (PROTACs) have been utilized to overcome drug resistance by degrading mutant EGFR in non-small cell lung cancer (NSCLC) therapy. However, their therapeutic efficacy is often compromised by the complex tumor microenvironment, which can lead to the reduced sensitivity of lung cancer cells to PROTACs. In this study, oxygen supplier (CaO2) and PROTAC co-loaded liposomes (LCP) are developed for simultaneously promoting EGFR degradation and hypoxic microenvironment alleviation. Calcium peroxide (CaO2) can release oxygen to modulate the hypoxic microenvironment, thereby reducing HIF-1α expression and enhancing the sensitivity of lung cancer cells. Compared with PROTACs administered alone, LCP exhibited enhanced tumor cell killing effect, improved protein degradation capacity, and superior tumor growth inhibition in NSCLC animal models. Mechanistic analysis reveals that LCP modulates hypoxia-associated proteins, including FGFR1, ERK, and TGF-α, contributing to the enhanced therapeutic efficacy. The LCP developed herein offers a strategy for enhancing NSCLC therapy by remodeling the hypoxic tumor microenvironment.