Folic Acid-functionalized Liposomal Covalent Organic Framework for Enhanced Photothermal Cancer Therapy

Introduction: ICG suffers from poor photostability and rapid clearance in PTT. This study constructs an FA-modified, pH/NIR responsive COF nanodelivery system for targeted ICG delivery and precise controlled release. Methods: FA-Lip-IC was prepared by solvent evaporation. TEM and dynamic light scattering characterized morphology and size. Drug release was evaluated under different pH conditions with or without an 808 nm laser. Photothermal properties were assessed by an 808 nm laser. CLSM and flow cytometry analyzed FR-mediated cellular uptake. Biocompatibility was evaluated using an MTT assay, a hemolysis test, and a zebrafish model. Pharmacokinetics was monitored by blood fluorescence intensity in rats. Results: FA-Lip-IC showed uniform spherical morphology with a size of 577.4 ± 9.42 nm. The cumulative drug release reached 92.56 ± 0.81% at pH 5.5 with NIR irradiation. FA modification increased cellular uptake by ID8 and 4T1 cells. Under 808 nm laser irradiation, FA-Lip-IC induced a local temperature increase of > 20°C, with significantly higher cytotoxicity than free ICG. Hemolysis rate was < 3%, normal cell viability > 87%, zebrafish hatching rate > 90%, and blood circulation time was prolonged. Discussion: This platform integrates the high loading capacity of COFs with liposome biocompatibility. FA targeting and pH/NIR-responsive release enhance treatment precision. A limitation is the lack of in vivo efficacy data. Conclusion: FA-Lip-IC combines photothermal stability, active tumor targeting, and stimuliresponsive release, offering a promising strategy to overcome the limitations of conventional PTT and advance precision cancer therapy.