Photodynamic therapy (
PDT) is a promising treatment modality for
tumor suppression. However, the hypoxic state of most solid
tumors might largely hinder the efficacy of
PDT. Here, a functional
covalent organic framework (COF) is fabricated to enhance
PDT efficacy by remodeling the
tumor extracellular matrix (ECM). Anti-fibrotic
drug pirfenidone (PFD) is loaded in an
imine-based COF (COFTTA-DHTA) and followed by the decoration of
poly(lactic-co-glycolic-acid)-poly(
ethylene glycol) (PLGA-PEG) to fabricate PFD@COFTTA-DHTA@PLGA-PEG, or
PCPP. After injected intravenously,
PCPP can accumulate and release PFD in
tumor sites, leading to down-regulation of ECM compenents such as
hyaluronic acid (HA) and
collagen I. Such depletion of
tumor ECM reduces the intratumoral solid stress, a compressive force exerted by the ECM and cells, decompresses
tumor blood vessels, and increases the density of effective vascular areas, resulting in significantly improved
oxygen supply in
tumor. Furthermore,
PCPP-mediated
tumor ECM depletion also enhances the
tumor uptake of subsequently injected Protoporphyrinl IX (
PPIX)-conjugated
peptide formed nanomicelles (NM-
PPIX) due to the improved enhanced permeability and retention (EPR) effect. Both the alleviated tumor hypoxia and improved
tumor homing of
photosensitizer (PS) molecules after
PCPP treatment significantly increase the
reactive oxygen species (ROS) generation in
tumor and therefore realize greatly enhanced
PDT effect of
tumor in vivo.