Mitochondria-Targeted MPDA Nanosystem Co-Delivering Evodiamine and IR820 for Chemo-Photothermal Therapy of Hepatocellular Carcinoma

Introduction: Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by considerable heterogeneity, aggressive invasiveness, and a high recurrence rate. Monotherapy often yields limited clinical efficacy, and evodiamine (EVO), a natural alkaloid with promising antitumor activity, is hindered by low bioavailability and potential systemic toxicity. Methods: A mesoporous polydopamine (MPDA)-based theranostic nanosystem was constructed for the co-delivery of EVO and the photothermal agent IR820. To enhance tumor specificity and minimize off-target toxicity, the platform was functionalized with cyclic RGD (cRGD) peptides for active tumor homing and triphenylphosphonium (TPP) for mitochondrial localization. The resulting IR820/EVO@MPDA-TPP/cRGD nanoparticles were characterized for drug loading, photothermal conversion stability, and fluorescence properties, and evaluated for antitumor efficacy and mechanistic actions in vivo. Results: The nanosystem demonstrated high drug loading efficiencies, excellent photothermal conversion stability, and robust near-infrared fluorescence emission suitable for real-time diagnostic tracing. Upon NIR laser irradiation, IR820/EVO@MPDA-TPP/cRGD exhibited potent synergistic anticancer activity and significantly inhibited tumor growth in vivo. Mechanistically, the combined photothermal and chemotherapeutic effects triggered severe mitochondrial dysfunction, leading to the collapse of mitochondrial membrane potential and subsequent release of pro-apoptotic factors. Discussion: The dual-targeting strategy effectively shifted cellular homeostasis toward programmed cell death while simultaneously engaging quality control pathways, underscoring a mitochondria-centered mechanism linking photothermal effect and chemotherapy. Conclusion: IR820/EVO@MPDA-TPP/cRGD represents a dual-targeting theranostic nanoplatform that integrates imaging and chemo-photothermal combination therapy. This strategy offers a promising and clinically relevant approach for advanced HCC. Nanoparticle system: synthesis, targeting and effects like ROS, autophagy, apoptosis.The image shows a nanoparticle delivery system involving multiple stages of synthesis and cellular effects. The synthesis process begins with MPDA, followed by IR820/EVO@MPDA, IR820/EVO@MPDA-cRGD and finally IR820/EVO@MPDA-TPP@cRGD. Components include EVO, IR820, cRGD and TPP. A mouse is shown receiving an injection, with nanoparticles targeting a tumor. Inside the cell, the nanoparticles are exposed to near-infrared light (NIR), leading to decreased mitochondrial membrane potential (Δψ) and ATP levels. This results in increased reactive oxygen species (ROS) production, triggering autophagy marked by LC3-II and apoptosis through cytochrome C and activated caspase pathways. Arrows indicate the flow of processes and interactions within the cell. Keywords: hepatocellular carcinoma, evodiamine, mesoporous polydopamine, photothermal therapy, drug delivery, mitochondria