The clinical utility of membrane-lytic peptides (MLPs) as cancer therapeutics is severely compromised by their inherent instability, rapid clearance, and non-specific toxicity, including hemolysis. We report a unimolecular nanoparticle platform, the Charge-Alternating Spherical MLP (CAS-MLP), engineered to overcome these barriers through a synergistic structural and chemical design. Structurally, MLPs are grafted as side chains onto a redox-responsive poly(disulfide) backbone, forming a bottlebrush architecture that enhances proteolytic stability and prolongs circulation. Chemically, the MLPs' lytic activity is temporarily neutralized using detachable charge-alternating (CA) reagents via maleamic anhydride-amine chemistry. This “smart” shielding minimizes hemolysis and off-target toxicity while also serving as a conjugation point for cancer-specific ligands, enabling precisely tuned targeting. This platform is designed for sequential intracellular activation: after ligand-mediated uptake, the acidic endosomal environment triggers CA reagent detachment, while the reductive cytosol degrades the poly(disulfide) backbone. This dual-stimuli-triggered disassembly selectively restores the MLP's lytic function inside the cancer cell. In vivo, the CAS-MLP platform demonstrates potent tumor growth suppression with negligible side effects. By leveraging the abundant lysine residues of MLPs, this approach provides a versatile and effective solution to key challenges in MLP-based therapy.
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