ROS-responsive polyethylenimine-phenylboronic acid-bovine serum albumin nanoparticles for targeted siMETTL3 delivery in hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC) is highly aggressive and chemoresistant, severely limiting the clinical efficacy of current therapies. Methyltransferase-like 3 (METTL3), a key regulator of N6-adenosine methylation (m6A), is overexpressed in HCC and promotes its malignant progression, serving as a promising therapeutic target. siMETTL3 can specifically silence METTL3 but suffers from poor in vivo stability, nuclease degradation, and low delivery efficiency, hindering its clinical translation. To address these issues, we developed a reactive oxygen species (ROS)-responsive nanocarrier termed PEI-PBA-BSA for efficient siMETTL3 delivery, and systematically evaluated its physicochemical properties, tumour-targeting ability, and anti-HCC efficacy. Our results demonstrated that the nanocarrier encapsulated and protected siMETTL3. Through enhanced cellular uptake and ROS-triggered controlled release in the tumour microenvironment (TME), this nanocarrier efficiently silenced METTL3. In vitro, the nanoparticles significantly inhibited hepatoma cell proliferation, migration, invasion, and stemness. In vivo, the nanoparticles effectively suppressed tumour growth (with a tumour inhibition rate of up to 68%) and demonstrated good biosafety. In summary, PEI-PBA-BSA@siMETTL3 (PPB@siM3) represents a promising nanoplatform that mediates targeted and controlled siRNA release via TME-specific ROS responsiveness, overcoming core bottlenecks in traditional METTL3 gene therapy.