Biomimetic nanocrystals co-deliver paclitaxel and small-molecule LF3 for ferroptosis-combined chemotherapy for gastric cancer.

Combination chemotherapy is considered more effective than monotherapy in enhancing clinical outcomes. Ferroptosis, a unique form of regulated cell death, has been demonstrated to inhibit tumor growth and progression. Consequently, combining ferroptosis with chemotherapy represents a promising and innovative approach to antitumor therapy. In this study, we developed a novel TMTP1-modified biomimetic nanocrystal (TRNC@P + L) for the co-delivery of PTX and LF3, aiming to achieve ferroptosis-combined chemotherapy in gastric cancer. TRNC@P + L, which incorporates a tumor-homing peptide-modified red blood cell membrane, demonstrated efficient tumor targeting, prolonged circulation, enhanced drug bioavailability, and reduced non-specific toxicities of free PTX and LF3. By utilizing the synergistic effects of PTX and LF3, TRNC@P + L combination therapy significantly inhibited tumor growth, as demonstrated by both in vitro and in vivo studies. Mechanistically, TRNC@P + L triggers ferroptosis in tumor cells by downregulating GPX4 expression, the promotion of ROS accumulation, and the enhancement of lipid peroxidation. These processes synergistically enhance the anticancer efficacy of PTX.