Multitriggered Tumor‐Responsive Drug Delivery Vehicles Based on Protein and Polypeptide Coassembly for Enhanced Photodynamic Tumor Ablation

Tumor‐responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein‐based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross‐linking and surface polyethylene glycol coupling, can be used as versatile tumor‐responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6‐encapsulated nanospheres (Ce6‐Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6‐Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6‐Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6‐Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6‐Ns and the biocompatibility of Ce6‐Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles.