Tumor microenvironment pH-responsive size-transformable peptide self-assembling nanocarriers for tumor-specific treatment.

Peptide-based drug carriers with exceptional biodegradability offer promising avenues for tumor-targeted therapy. Nonetheless, almost all existing drug carriers harness receptor recognition to target tumors, which ultimately fall short in addressing tumor heterogeneity. Such a strategy requires intricate chemical modifications for carriers to selectively bind to specific receptors. While these modifications may induce long-term toxicity, tumor receptors are not absolutely specific but also exist in normal cells. Thus, precision therapeutic agents may inadvertently harm healthy cells as well. Tumors possess a distinctive weak acidic (pH 6.0-6.8) tumor microenvironment (TME) that contrasts with normal tissues (pH 7.4). Hence, we developed a TME pH-triggered multilevel self-assembling peptide with simple modifications. The drug-encapsulating self-assembled peptide is size transformable from aggregates (1.56 μm) at pH 7.4 to positively charged nanomicelles (~100 nm) at an acidic TME by protonation, which avoids being taken up by normal cells but could readily enter tumor cells, allowing TME pH-triggered tumor-specific therapy. This study establishes a breaking strategy of using peptide for TME-based tumor-specific treatment and advances the medical applications of peptide nanomaterials.