Unveiling the Multiple Tumor-Targeted Impairments of Covalent-Organic Framework-Switched Photothermal Shielding Nanoparticles

Covalent organic framework (COF) receives great attention in biomedical applications due to its variable compositions and ordered structures. However, its targeted design to achieve desirable physiological functions especially for cancer treatments remains elusive. Herein, PEGylated COF with tumor-specific TKD peptide modification is uniformly coated on photothermal mesoporous carbon nanospheres via polyethyleneimine-mediated interface polymerization to construct a multifunctional core-shell nanoparticle (OPCPT). Physicochemical studies demonstrate near infrared (NIR)-blocking ability of the crystalline COF shells under physiological conditions, whereas COF is degraded under the acidic tumor microenvironments (TME). Subsequently, the nanoparticle charge is reversed and the COF monomers can produce ¹O₂/O₂. As a result, OPCPT, activated in the TME due to the shell dissociation, penetrates deeply into tumors through positive charge-mediated/lysosome rupture-mediated transcytosis and recovers its NIR-heating potential for tumor-specific photothermal therapy. Moreover, the TME-triggered ¹O₂ significantly depresses the lysosome autophagy via membrane destruction, and selectively damages the mitochondria to promote the cytochrome C release-activated apoptosis and ATP deficiency-inhibited tumor metastasis. Particularly, this unique O₂ generation mechanism relieves the tumor hypoxia upon the reactive oxygen species therapy and downregulates hypoxia-inducible factor and its downstream proteins, which all contribute to augmented tumor therapy. The findings represent a remarkable unveiling of the potential of COF-based nanomaterials for extended biomedical applications.