A Broad‐Spectrum Tumor‐Penetrating Peptide WKASC: Design, Screening, and Platform Development for Cancer Therapy

ABSTRACT Conventional cancer therapies are often limited by inadequate drug accumulation in tumors, drug resistance, and systemic toxicity. Cell‐penetrating peptides (CPPs) offer a promising strategy to enhance intracellular drug delivery. In this study, we designed a novel tumor‐penetrating peptide, P3 (sequence: Trp‐Lys‐Ala‐Ser‐Cys), which demonstrated exceptional transmembrane efficiency with a broad‐spectrum penetration profile across various tumor cell lines (including HeLa, HGC‐27, and A549 etc.). Notably, it achieved an internalization rate of 47.4% in A549 cells within 15 min. This peptide was further engineered into an amphiphilic polymer, P3‐Mal‐PEG‐PCL, which self‐assembled into pH‐responsive micelles. Doxorubicin (DOX) was encapsulated within these micelles to form DOX@P3P, which was subsequently coated with hyaluronic acid (HA) to create the final actively targeted nanoparticles, DOX@P3P@HA (PHA NPs), leveraging the cluster of differentiation 44 (CD44) receptor overexpression on cancer cells. The PHA NPs displayed excellent biosafety, colloidal stability, and improved drug distribution. In a murine tumor model, treatment with PHA NPs resulted in a remarkable 76.6% reduction in tumor volume, underscoring its potent antitumor efficacy and highlighting its potential as a robust platform for targeted cancer chemotherapy.