NIR-Responsive Mitochondria-Targeted Liposomal Covalent Organic Framework for Combined Cancer Therapy

Background: Nanoplatform-based combination therapy offers a promising route for enhanced cancer therapy. Despite the advance of nanomedicine, the precise subcellular co-delivery and controlled release of combinatorial therapeutic agents remain a significant challenge. Methods: Herein, a near-infrared (NIR)-responsive mitochondria-targeted nanoplatform (HTL@CIC) was firstly developed for combined cancer therapy. Briefly, curcumin (CUR) and indocyanine green (ICG) were co-loaded into a lipid-coated covalent organic framework (COF), followed by surface modification with a hyaluronic acid-triphenylphosphonium conjugate (HT). The characterization, release behavior, cellular uptake, mitochondrial targeting, anticancer activity, and safety of the developed nanoparticle were investigated. Moreover, the underlying mechanisms of tumor targeting ability and anticancer effect were explored. Results: The HTL@CIC exhibited good stability and improved photothermal performance. Moreover, it showed prolonged circulation, while the HT moiety simultaneously conferred CD44-mediated tumor targeting and triphenylphosphonium-directed mitochondrial accumulation. Besides, NIR laser irradiation could trigger a rapid release of CUR and ICG, which subsequently produced an enhanced antitumor effect combining chemotherapy and photothermal therapy (PTT). Both in vitro and in vivo studies demonstrated the superior antitumor activity of HTL@CIC. The improved antitumor outcome likely resulted from reactive oxygen species (ROS) overproduction and mitochondrial damage. Furthermore, HTL@CIC exhibited favorable erythrocyte compatibility as well as good biosafety in the mice and zebrafish. Conclusion: The NIR-responsive HTL@CIC achieves tumor- and mitochondria-targeted controlled release of CUR and ICG, enhancing anticancer efficacy with good safety. Therefore, this developed platform may offer a novel and promising strategy for subcellular precision cancer therapy.