Biomimetic Nanoparticles with Dual Targeting for Hepatocellular Carcinoma Promote Tumor Immune System Activation by Enhancing Extracellular ATP Homeostasis

Chemodynamic therapy (CDT) plays a crucial role in transforming the tumor microenvironment by inducing immunogenic cell death (ICD) to eliminate cancer cells. Nonetheless, the effectiveness of CDT in eliciting antitumor immunity is somewhat constrained. The persistent presence of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), in the tumor offsets some of the ICD effects triggered by CDT. Moreover, extracellular adenosine triphosphate (eATP), a crucial damage-related molecular pattern that initiates ICD, is quickly degraded into adenosine, an immunosuppressive metabolite, by CD39 molecules prevalent in the tumor environment, thereby evading immune destruction. In this report, we introduce a nanomaterial, CP@HMM (copper-doped carbon dots and POM1 encapsulated by a hybrid membrane composed of Hepa1-6 and a MDSCs membrane), which targets liver cancer cells and MDSCs and inhibits the ATP-adenosine metabolic pathway. The hybrid membrane, derived from hepatocellular carcinoma (HCC) cells and MDSCs, facilitates the targeted delivery of copper-doped carbon dots (Cu-CDs) to these cells. The potent Fenton-like reactions and the cytotoxicity of copper ions allow CP@HMM to not only kill tumor cells but also eradicate intratumoral MDSCs. Additionally, the CD39 inhibitor POM1 within the system prevents the degradation of eATP induced by the Cu-CDs treatment. This leads to increased eATP levels and drives antitumor immunity activation, including macrophage pyroptosis and dendritic cell maturation, which suppresses primary tumor progression and distant metastases while fostering immune memory to prevent tumor recurrence. Our findings suggest that CP@HMM is an effective drug-delivery system and offers a potential therapeutic alternative for patients with HCC, promising advancements in combined tumor immunotherapy strategies.