Poly(amino acid)-based design principle for pH-responsive tumor delivery

Selective tumor delivery that maximizes antitumor efficacy while minimizing systemic toxicity remains a major challenge in cancer therapy. Among tumor-specific microenvironmental features, extracellular acidosis is a ubiquitous hallmark of solid tumors and provides a compelling rationale for the design of tumor-targeted delivery systems. In this regard, this review focuses on poly(amino acid)-based materials for pH-responsive tumor delivery. Poly(amino acids) offer high flexibility in molecular design, as well as biocompatibility, enabling precise tuning of physicochemical and biological properties through sequence engineering and/or side-chain modification. We first summarize the biological mechanisms and clinical evidence underlying tumor acidification, emphasizing its spatial heterogeneity and functional relevance. Subsequently, we review key molecular design strategies involving peptides, proteins, and synthetic poly(amino acids) as versatile pH-responsive platforms for tumor-targeted delivery.