Cell-Penetrating Peptide Conjugated Polyzwitterion-Drug Enhances Tumor Retention

The dense microenvironment of triple-negative breast cancer (TNBC) poses a formidable barrier to nanomedicine penetration, rendering selective tumor retention critical for effective drug delivery. Cell-penetrating peptides (CPPs)-PEG polymers improve SN38 cellular uptake but lack tumor selectivity. We employed a quantitative structure–activity relationship (QSAR)-driven strategy to screen a combinatorial CPPs library for tumor microenvironment responsiveness. We elucidated that proline residues induce peptide bending and steric effects, resulting in PEG shield to limit cargo cellular entry. Eliminating these residues abrogated structural kinks, yielding a linearized peptide topology that effectively pierced the PEG shell to engage anionic membrane receptors, thereby enhancing tumor penetration and intracellular accumulation. Consequently, the optimized TAT 12 -PEG-SN38 micelles prolonged blood circulation and suppressed TNBC growth and metastasis. Furthermore, combination treatment with JQ-1 attenuated immune evasion. Overall, peptide structure engineering overcomes the PEG barrier, providing a practical strategy for developing novel peptide–drug conjugates.