Synergistic p53 Pathway Activation Through Sono‐Gene Therapy Induced by Ultrasound‐Triggered Theranostic Mesoporous Nanoparticles

ABSTRACT

Hepatocellular carcinoma (HCC) poses a significant global health burden due to its high mortality. The modest efficacy of single‐agent treatments is spurring the quest for combinatorial approaches. Sonodynamic therapy and gene therapy offer promising therapeutic approaches, yet they are limited by restricted tumor specificity and inefficient delivery. In this work, we developed a multifunctional mesoporous silica‐based nanoplatform co‐delivering indocyanine green (ICG) and CD24 small interfering RNA (siRNA) (siCD24), and the surface was engineered with lactobionic acid (LA) to enable active targeting and 2,3‐dimethylmaleic anhydride (DMMA) to confer tumor microenvironment‐responsive charge reversal, thereby enhancing specific accumulation and release. Under ultrasound irradiation, the nanoplatform concurrently activates dual mechanisms: ICG‐mediated sonodynamic action generates reactive oxygen species, while synchronized CD24 silencing modulates downstream effectors, such as p14 alternative reading frame and MDM2. This leads to coordinated regulation of the p53, resulting in the upregulation of the Cleaved caspase‐3 and p21, alongside the downregulation of Cyclin D1. Evaluations in vitro and in vivo demonstrated that combinatorial therapy exerts superior antitumor efficacy compared to monotherapy. Notably, the nanoparticles significantly enhanced ultrasound imaging. Our work validates the concept of a unified theranostic platform for sono‐gene therapy and ultrasound imaging, representing a promising advance in HCC treatment.