Engineering Liver-Targeted Carbon Dots for Hepatic Injury Therapy

Abstract With growing incidence and limited treatment modalities, drug-induced liver injury (DILI) has become a prominent unmet clinical challenge. Despite being the primary clinical hepatoprotective agent, N-acetylcysteine (NAC) is severely constrained by its insufficient therapeutic efficacy and lack of liver-targeting specificity. Herein, we present the development of liver-targeted carbon dots (HTGN-CDs) as a precision nanotherapeutic against DILI. On the one hand, GN-CDs were synthesized using NAC and glucose as precursors, with NAC incorporation significantly strengthening the antioxidative capacity of CDs. On the other hand, surface functionalization with glycyrrhetinic acid-polyethylene glycol (GA-PEG) endowed the GN-CDs with enhanced hepatocyte-targeting capability, thereby promoting their accumulation in the liver. In vitro assays confirmed the potent antioxidant and anti-inflammatory activity of GN-CDs, while in vivo studies in acetaminophen (APAP)-overdose mice demonstrated that HTGN-CDs significantly reduced hepatocyte necrosis and lowered key biochemical indicator levels, with efficacy superior to the clinical standard NAC. Mechanistically, HTGN-CDs mitigated oxidative stress via the restoration of antioxidant enzyme activity and suppressed inflammation by blocking pro-inflammatory cytokine release and macrophage infiltration. Safety assessments verified excellent biocompatibility of HTGN-CDs, with no detectable hemolytic activity, hematological abnormalities, or organ toxicity observed. Collectively, our findings highlight HTGN-CDs as a promising multifunctional nanotherapeutic for DILI, with substantial potential for clinical translation.