Engineering a porphyrin COFs encapsulated by hyaluronic acid tumor-targeted nanoplatform for sequential chemo-photodynamic multimodal tumor therapy

Numerous barriers hinder the entry of drugs into cells, limiting the effectiveness of tumor pharmacotherapy. Effective penetration into tumor tissue and facilitated cellular uptake are crucial for the efficacy of nanotherapeutics. Photodynamic therapy (PDT) is a promising approach for tumor suppression. In this study, we developed a size-adjustable porphyrin-based covalent organic framework (COF), further modified with hyaluronic acid (HA), to sequentially deliver drugs for combined chemo-photodynamic tumor therapy. A larger COF (P-COF, approximately 500 nm) was loaded with the antifibrotic drug losartan (LST) to create LST/P-COF@HA (LCH), which accumulates at tumor sites. After injection, LCH releases LST, downregulating tumor extracellular matrix (ECM) component levels and decreasing collagen density, thus reducing tumor solid stress. Additionally, the reactive oxygen species (ROS) generated from LCH under 660 nm laser irradiation induce lipid peroxidation of cell membranes. Owing to its larger particle size, LCH primarily functions extracellularly, paving the way for subsequent treatments. Following intravenous administration, the smaller COF (p-COF, approximately 200 nm) loaded with doxorubicin (DOX) and modified with HA (DOX/p-COF@HA, DCH) readily enters cells in the altered microenvironment. Within tumor cells, ROS generated from DCH facilitates PDT, while the released DOX targets cancer cells via chemotherapy, triggered by disulfide bond cleavage in the presence of elevated glutathione (GSH) levels. This depletion of GSH further enhances the PDT effect. Leveraging the size-tunable properties of the porphyrin COF, this platform achieves a multifunctional delivery system that overcomes specific barriers at optimal times, leading to improved outcomes in chemo-photodynamic multimodal tumor therapy in vivo.