A self-motivated carrier free nanoplatform for synergistic photodynamic and ferroptosis-based therapy for targeted antitumor treatment

Photodynamic therapy (PDT) has been extensively investigated as an alternative cancer treatment; however, its efficacy is limited by the low oxygen content and excess glutathione (GSH) in tumor tissues. With the emergence of ferroptosis, which also impacts redox homeostasis, a combined PDT-ferroptosis approach holds promise for amplifying the efficacy of both treatments. However, concerns persist regarding biocompatibility and tumor-specific release. Here, we report a self-motivated co-nanoassembly for combined PDT and ferroptosis-driven tumor therapy. We first modify linoleic acid with protoporphyrin IX to form a lipidic derivative (denoted as PLA) and develop a light-boosted carrier-free nanoplatform (PLA@R NPs) by co-assembling the ferroptosis inducer RAS-selective lethal 3 (RSL3) and PLA. Upon light irradiation, reactive oxygen species produced by PDT trigger linoleic acid peroxidation, leading to the destruction of the nanoparticles and the release of RSL3. The rapid release of RSL3 enhances PDT sensitivity by depleting GSH and utilizing the Fenton reaction to supplement oxygen. Additionally, PDT accelerates lipid peroxidation, further inducing ferroptosis. This self-motivated effect increases oxidative stress in tumor tissues, as confirmed by a tumor-on-a-chip model. Moreover, the in vivo therapeutic effect with the PLA@R NPs is significant, demonstrating the promising potential of combining PDT and ferroptosis using a light-boosted and self-motivated nanoplatform.