Hypoxia-Responsive Thio-Perylene Diimides Delivered via pH-Responsive Polypeptide Nanoparticles: Toward a Combination of NIR Photothermal Therapy and Chemotherapy.

Developing responsive therapeutic systems based on the tumor microenvironment is crucial for efficient and specific treatments. However, how to achieve sensitive response and efficient anticancer bioactivity remains a challenge. Here, tumor-responsive polypeptide nanoparticles encapsulating thio-perylene diimides are constructed. Anticancer peptides were released through the hydrolysis of acid-labile amide bonds to induce cell apoptosis, while thio-perylene diimide radical anions with up to 67% NIR photothermal conversion efficiency could be generated through a hypoxia-induced biological reduction process. Thus, this approach enables the development of a dual-response nanomedicine to achieve combinational NIR photothermal therapy and chemotherapy. In the A549 lung cancer cell-derived xenograft model established in BALB/c nude mice, the tumor inhibition rate reached 68.0%. In addition, tumor-responsive polypeptide nanoparticles also possessed excellent biocompatibility. This line of research provides a new method for the construction of highly sensitive tumor microenvironment-responsive therapeutic systems and contributes to the development of comprehensive multimodal treatment approaches.