Cross-Linked Lipoic Acid Trisulfide Nanoparticles: Revisiting H 2 S Intervention as a Stand-alone Modality for Cancer Therapy

Despite the pleiotropic anticancer potential of the endogenous gasotransmitter hydrogen sulfide (H2S), achieving sustained and adequate intratumoral H2S supply remains a persistent challenge, hindering its advancement as a stand-alone therapeutic modality. Herein, we introduce cross-linked lipoic acid trisulfide nanoparticles (cLATN) that integrate both the H2S donor and transporter within a single precursor, wherein each unit theoretically yields one molecule of H2S, enabling stoichiometric H2S loading. cLATN effectively enter tumor cells via thiol-mediated uptake and are depolymerized by glutathione to trigger sufficient H2S release in tumor tissues for more than 48 h, far surpassing current H2S-based anticancer agents, which generally persist for only a few hours. Therapeutically, cLATN achieve an impressive tumor inhibition rate of 83% with favorable biocompatibility, far exceeding the clinical agent doxorubicin in both efficacy and safety. This work affirms its potential for cancer treatment, renewing interest in positioning H2S intervention as a stand-alone modality toward broader clinics.