Honokiol‐loaded nanomicelles reprogram senescence and immune evasion in hepatocellular carcinoma via SIRT3 ‐mediated mitochondrial stabilization

Abstract Hepatocellular carcinoma (HCC) is a major cause of cancer‐related deaths. Advanced‐stage patients face poor prognosis due to chemotherapy resistance and an immunosuppressive tumor microenvironment (TME). Cellular senescence, marked by the senescence‐associated secretory phenotype, promotes tumor progression and immune evasion. Although honokiol (HKL) shows strong antitumor activity, its clinical use is limited by poor solubility, rapid clearance, and low bioavailability. Here, we report HKL‐loaded poly(ethylene glycol)‐poly(ε‐caprolactone)‐poly(ethylene glycol) triblock copolymer nanomicelles (HKL‐nm) as a multifunctional nanotherapeutic platform. HKL‐nm exhibited a uniform spherical shape with a diameter of 60.93 ± 5.7 nm, near‐neutral charge (−0.28 ± 0.1 mV), and high encapsulation efficiency (85.9 ± 4.9%). It enabled sustained drug release (70.04 ± 6.2% over 200 h) and significantly improved oral pharmacokinetics (area under the curve increased 6.26‐fold and C max increased 4.06‐fold). Specifically, the HKL drug concentration at the tumor site was enhanced by 3.52‐fold. Mechanistically, HKL‐nm suppressed senescence markers (p53, p16, and p21) and senescence‐associated β‐galactosidase positivity via a Sirtuin 3‐dependent pathway, inhibiting cytoplasmic mitochondrial DNA leakage and cGAS‐STING signaling. In Hepa1‐6 cells xenografts, combination therapy with HKL‐nm and the senolytic cocktail dasatinib + quercetin achieved tumor volume reduction, with transcriptomic analysis validating enrichment of immune activation pathways. This was accompanied by enhanced infiltration of CD8 + cytotoxic T cells and mature dendritic cells, coupled with profound suppression of myeloid‐derived suppressor cells. By integrating nanodelivery, senescence modulation, and immuno‐oncology, HKL‐nm represents a promising strategy to overcome therapeutic resistance in HCC, providing a preclinical basis for translation to solid tumors.