Biodegradable fibrin-based gel-assisted tumor-targeted nanoparticles self-enhanced ferroptosis and DOX-induced chemotherapy

Currently, while intravenous chemotherapy effectively targets tumor lesions, it also causes unavoidable systemic toxicity due to drug metabolism in the bloodstream and the toxicity to normal cells. To address this problem, an injectable and biodegradable fibrin-based gel was employed as a pharmacy scaffold, cladding FDA-approved DOX-loaded and hyaluronic acid (HA)-modified nanoparticles (DOX&FeP-HA@gel), aiming to achieve local tumor therapy through the combination of ferroptosis-DOX mediated self-enhancement therapy. The DOX&FeP-HA exhibited remarkable CD44 bio-targeting, medium stability, TME-triggered degradation, and continued release of drugs, achieving approximately 80 % cumulative release within 48 h. During this process, the released DOX induced apoptosis and generated abundant H 2 O 2 by mitochondrial activity. Simultaneously, intracellular H 2 O 2 reacted with Fe 2+ to produce highly toxic OH. Moreover, DOX&FeP-HA not only consumed GSH but also reduced GPX4 expression in tumor cells, thereby amplifying ferroptosis. To anchor nanoparticles in tumor tissue, an injection that utilizes fibrin-based gel was introduced. In live experiments, 4T1 tumor-bearing mice received optimal therapeutic outcomes with DOX&FeP-HA@gel treatment, achieving a 100 % survival rate over 30 days according to Kaplan-Meier survival analysis. Overall, a strategy of in situ injection gel carrying multifunctional nanoparticles was proposed, offering a promising new approach to tumor treatment with substantial potential for clinical applications.