Self-Assembly of Peptide-Lipid Platinum(IV) Prodrug Amphiphile for αvβ3 Integrin-Targeting Chemotherapy

Passive-targeting nanodelivery systems for cytotoxic drugs are often limited by the heterogeneity of the enhanced permeability and retention (EPR) effect, off-target toxicity, and monotherapy resistance. Peptide-drug conjugates (PDCs) offer a structurally precise and bio-programmable strategy to compensate for these drawbacks. Herein, we report a structurally precise platinum (Pt)-based PDC design that integrates axial-ligand engineering with carrier-free self-assembly. Axial covalent modification of Pt^IV with a hydrophobic alkyl chain and a cyclic RGD targeting peptide (c(RGD)fk) affords a structurally well-defined amphiphilic prodrug that spontaneously assembles into stable lipid nanoparticles (NPt^IVcRGD). These nanoparticles exhibited high α_vβ₃ integrin-mediated selectivity, resulting in superior tumor accumulation. Within the reductive tumor microenvironment, the Pt^IV center was converted to cytotoxic Pt^II, resulting in pronounced DNA damage and a tumor growth inhibition rate of 78%, significantly outperforming cisplatin. Notably, systemic toxicity was markedly attenuated, as evidenced by minimal body weight loss and reduced hepatic and renal damage. This study establishes a structurally simplified PDC-based chemotherapy paradigm for Pt drugs. By axially functionalizing a Pt^IV prodrug with an active targeting peptide and leveraging its carrier-free self-assembly properties, this approach enhances antitumor efficacy while significantly minimizing off-target toxicity.