A medicine and food homology-derived self-assembled capsaicin nano-prodrug modulates ferroptosis for HCC immunotherapy via peroxynitrite generation

• A Medicine and Food Homology (MFH) notion is used to generate a capsaicin nano-prodrug. • The self-assembled nanoprodrug enables targeted delivery of capsaicin and nitric oxide to tumors. • The combination therapy generates peroxynitrite to boost ferroptosis via glutathione depletion and lipid peroxidation. • This nanoprodrug activates antitumor immunity, achieving a tumor inhibition rate of 93.4% in a murine liver cancer model. Inspired by Medicine and Food Homology (MFH), developing natural dietary therapeutics holds translational potential but is often limited by unclear mechanisms. Herein, we report a capsaicin (Cap)-derived binary prodrug, Bio-SS-Cap, featuring a disulfide-linked biotin (Bio). The amphiphilic structure enables further self-assembly of Bio-SS-Cap into stabilized nanoparticles (NPs) with passive and active dual tumor targeting properties. Further encapsulation of a hydrophobic nitric oxide (NO) donor, isosorbide dinitrate (ISDN) by Bio-SS-Cap NPs affords ISDN-loaded nanoprodrugs, ISDN@Bio-SS-Cap NPs. Intracellular glutathione (GSH)-triggered cleavage of the disulfide links promotes particulate dissociation for simultaneous release of Cap and ISDN that produces reactive oxygen species (particularly superoxide anion (O 2 •− )) and NO, respectively. More importantly, NO further reacts with O 2 •− to generate peroxynitrite (ONOO − ) for enhanced ferroptosis induction via GSH depletion, impaired regeneration, and lipid peroxidation. Together with the reactive oxygen and nitrogen species (RONS)-triggered immunogenic cell death (ICD), the ISDN@Bio-SS-Cap NPs-modulated enhanced ferroptosis promotes M2-to-M1 macrophage polarization and activates T cell infiltration for the innate-adaptive immunity loop activation, which leads to a tumor inhibition rate (TIR) of 93.4 % in a murine HCC model. Overall, this MFH-inspired self-assembled Cap nanoprodrug holds great translation potentials for potent ferroptosis-modulated immunotherapy of HCC via peroxynitrite generation.