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

ABSTRACT 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 IV cRGD). These nanoparticles exhibited high α v β 3 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.