Synergistic p53 Pathway Activation Through Sono-Gene Therapy Induced by Ultrasound-Triggered Theranostic Mesoporous
Yading Zhao1, Lu Guo1, Dandan Shi1
1Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, China.
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.
Insights
This study introduces a novel nanoplatform for hepatocellular carcinoma (HCC) treatment, combining sonodynamic and gene therapy. The dual-action approach demonstrated superior antitumor effects and enhanced ultrasound imaging capabilities.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Hepatocellular carcinoma (HCC) presents a major global health challenge with high mortality rates.
- Current single-agent therapies for HCC show limited efficacy, driving the need for innovative combinatorial treatments.
- Sonodynamic therapy and gene therapy offer potential but face challenges in tumor specificity and delivery efficiency.
Purpose of the Study:
- To develop a multifunctional nanoplatform for targeted HCC treatment.
- To co-deliver indocyanine green (ICG) for sonodynamic therapy and CD24 small interfering RNA (siRNA) for gene therapy.
- To integrate active targeting and tumor microenvironment-responsive release for enhanced therapeutic outcomes and theranostic capabilities.
Main Methods:
- Engineered a mesoporous silica nanoplatform co-delivering ICG and siCD24.
- Surface modification with lactobionic acid (LA) for active targeting and 2,3-dimethylmaleic anhydride (DMMA) for charge reversal.
- Investigated ultrasound-triggered dual mechanisms: ICG-mediated sonodynamic action and CD24 silencing, assessing downstream molecular effects (p53 pathway, apoptosis, cell cycle markers).
- Evaluated therapeutic efficacy in vitro and in vivo, alongside ultrasound imaging enhancement.
Main Results:
- The nanoplatform successfully co-delivered ICG and siCD24, achieving targeted accumulation and controlled release.
- Ultrasound irradiation activated synergistic sono-gene therapy, generating reactive oxygen species and downregulating CD24.
- This combinatorial approach modulated the p53 pathway, leading to increased apoptosis (Cleaved caspase-3) and cell cycle arrest (p21), while decreasing proliferation (Cyclin D1).
- Demonstrated superior antitumor efficacy compared to monotherapy and significantly improved ultrasound imaging.
Conclusions:
- The developed nanoplatform represents a promising theranostic strategy for HCC.
- Combined sonodynamic and gene therapy, facilitated by targeted and responsive nanocarriers, offers enhanced antitumor efficacy.
- This approach holds potential for advancing HCC treatment through integrated therapy and diagnostics.
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