Polymer-engineered liposome-delivered Ebselen against tumor through GSH/H₂O₂-responsive disruption of redox homeostasis and direct p53 activation.

Abstract

Ebselen (EbSe), an organic selenium-based compound with potential antitumor activity, faces great challenges of poor aqueous solubility, which impairs its bioavailability and exacerbates potential toxicity. Liposomes, as established clinical tools for delivering small molecule drugs, could help improve the therapeutic effectiveness by overcoming their aqueous solubility limitations to reduce side effects and increase accumulation in tumor tissue. In this study, we engineered a novel nano-delivery system (EbSe@LNP) using clinically validated cationic liposomes, ionizable lipids, and amphiphilic polymers as carrier for loading EbSe to improve solubility of EbSe and address compromised antitumor efficacy. By monitoring the EbSe@LNP solution for a long time, we observed that EbSe@LNP exhibited stable dispersion, significantly improving the aqueous solubility of EbSe. Furthermore, EbSe@LNP accumulated in tumor cells by specifically recognizing the membrane protein integrin α4 (Itga4), and released EbSe reacted with GSH and H₂O₂, breaking redox balance, inducing mitochondrial damage and facilitating cell apoptosis. Simultaneously, released EbSe activated p53 signaling pathway for triggering mitochondrial dysfunction to induce tumor cell death. In vivo experiments demonstrated that EbSe@LNP regulates immune cell ratios in tumor and spleen, effectively combating cancer progression. Collectively, this study not only offers a nano-delivery strategy to overcome the poor aqueous solubility of EbSe, but also elucidates its underlying antitumor mechanisms, offering a strong scientific foundation for its clinical translation.