Assembly Module-Empowering Lipid-Prodrug Nanoamplifier for Enhancing Ferroptosis-Driven Cancer Treatment

Ferroptosis has been widely explored as a promising cancer therapeutic target. Conventional ferroptosis induction relies on inhibiting glutathione peroxidase 4 (GPX4) to promote lipid peroxide accumulation. However, its efficacy is often limited by insufficient endogenous unsaturated lipids in tumor cells. To address this limitation, we developed a lipid-prodrug nanoamplifier (SIM-SS-LA NAs), composed of disulfide-linked linoleic alcohol and simvastatin (SIM) to enhance ferroptosis. Significant, the modularity of the prodrug not only promotes the assembly of the SIM but also amplifies its ferroptosis effect. In the highly reductive tumor microenvironment, disulfide bonds are cleaved, releasing SIM and LA. Notably, the released LA acts as an exogenous substrate, substantially increasing lipid peroxide accumulation and synergizing with SIM-mediated GPX4 inhibition to amplify ferroptosis. As expected, the lipid-prodrug nanoamplifier showed potent ferroptosis-driven antitumor activity in a 4T1 breast tumor-bearing mouse model, offering an efficient nanotherapeutic strategy for ferroptosis-based cancer therapy.