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

摘要

Covalent organic framework (COF) receives great attention in biomedicalapplications due to its variable compositions and ordered structures.However, its targeted design to achieve desirable physiological functionsespecially for cancer treatments remains elusive. Herein, PEGylated COFwith tumor-specific TKD peptide modification is uniformly coated on photothermalmesoporous carbon nanospheres via polyethyleneimine-mediatedinterface 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 monomerscan produce ~1O_2/O_2. As a result, OPCPT, activated in the TME due to theshell dissociation, penetrates deeply into tumors through positive chargemediated/lysosome rupture-mediated transcytosis and recovers its NIRheatingpotential for tumor-specific photothermal therapy. Moreover, theTME-triggered ~1O_2 significantly depresses the lysosome autophagy via membranedestruction, and selectively damages the mitochondria to promote thecytochrome C release-activated apoptosis and ATP deficiency-inhibited tumormetastasis. Particularly, this unique O_2 generation mechanism relieves thetumor hypoxia upon the reactive oxygen species therapy and downregulateshypoxia-inducible factor and its downstream proteins, which all contributeto augmented tumor therapy. The findings represent a remarkable unveilingof the potential of COF-based nanomaterials for extended biomedicalapplications.