Dihydroartemisinin (DHA), a widely used antimalarial agent, has clinical potential for the treatment of hepatic carcinoma. Although chemotherapy is indispensable for tumor therapy, it is generally limited by poor solubility, low efficiency, rapid clearance, and side effects. As an emerging treatment method, photothermal therapy (PTT) has many outstanding properties, but suffers from poor photostability of photosensitizer and incomplete ablation. Multimodal therapies could combine the advantages of different therapy methods to improve antitumor efficiency. Hence, we designed a nano-delivery system (ICG&DHA@ZIF-8) using zeolitic imidazolate framework-8 (ZIF-8) with a high porous rate and pH sensitivity property, to co-load DHA and indocyanine green (ICG). Dynamic light scattering and transmission electron microscopy were used to characterize the prepared nanoparticles. The photothermal conversion and drug release performances of ICG&DHA@ZIF-8 were investigated. In vitro antitumor efficacy and cellular uptake were studied. The mechanism of the combination treatment was studied by reactive oxygen species level detection and western blot assays. In vivo antitumor assays were then studied with the guidance of ex vivo imaging. The results showed that the ICG&DHA@ZIF-8 based combination therapy could efficiently kill hepatic carcinoma cells and suppress tumor growth. This research provides a potential nanodrug for the treatment of hepatic carcinoma.

Background: Hepatocellular carcinoma (HCC) remains challenging to treat because of the limited therapeutic efficacy and insufficient selectivity of conventional therapies. To overcome these limitations, multifunctional nanoplatforms integrating biomimetic strategies and combination therapy have attracted increasing attention. Single-modality therapies are often limited by insufficient therapeutic efficacy and restricted mechanisms of action, highlighting the need for biomimetic nanoplatforms that integrate combination therapeutic strategies for enhanced antitumor performance. Methods: Herein, a biomimetic strategy-based nanoplatform (DI-ZM) was constructed via a combination of ZIF-8 biomineralization, physical adsorption of dihydroartemisinin (DHA) and indocyanine green (ICG), followed by HepG2 cell membrane coating to achieve homologous interaction. This design enables integrated chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) within a single system. Results: The resulting DI-ZM nanoparticles exhibited a hydrodynamic diameter of approximately ~200 nm with good colloidal stability and high drug-loading capacity. Under 808 nm laser irradiation, DI-ZM achieved a temperature elevation to ~66 °C within 5 min, together with efficient ROS generation. Compared with uncoated nanoparticles, the biomimetic membrane coating significantly enhanced cellular uptake and homologous targeting ability, as confirmed by CLSM and flow cytometry analysis. Benefiting from the biomimetic membrane coating, DI-ZM further exhibited improved homologous targeting and cellular uptake, which contributed to enhanced intracellular ROS generation. This was accompanied by significant mitochondrial membrane depolarization and apoptosis rates exceeding 80% in HepG2 cells under laser irradiation, ultimately resulting in markedly enhanced cytotoxicity. In addition, the biomimetic membrane coating also enabled efficient penetration of DI-ZM into multicellular tumor spheroids, indicating its improved tumor-penetration capability. In vivo antitumor studies further revealed effective tumor suppression with a tumor inhibition rate of approximately 97%, along with acceptable systemic tolerance in HepG2 tumor-bearing mice. Conclusion: The biomimetic membrane-coated ZIF-8 nanoplatform integrating chemotherapy with ICG-mediated phototherapy (photothermal and photodynamic therapy) provides an effective strategy for the combination therapy against HCC.