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Lock-and-Shield Strategy Enables Stable and Stimuli-Responsive Tumor-Targeted Gene Delivery
Siqin Chen1, Chongzhi Wu2, Dandan Wang1
1Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore.
Abstract:
A major challenge to effective cancer gene therapy is the absence of delivery systems that both protect nucleic acids in circulation and release them efficiently inside tumor cells. Nucleic acids are rapidly degraded by nucleases, cleared from the blood, and poorly internalized due to size and charge. Existing vectors address parts of this problem but remain limited by cytotoxicity, instability, or inadequate tumor selectivity. Here, a lock-and-shield strategy integrating a hyaluronic acid Nanogel with a hybrid membrane shell (Nanogel@hMVs) is reported. The Nanogel "lock" physically entraps nucleic acids with high efficiency (81.6%-89.2%) and incorporates dual pH/redox-responsive linkers for controlled release under tumor-associated conditions. The membrane "shield", derived from tumor cell membranes and fusogenic lipids, reinforces systemic stability, preserves homotypic recognition, and mediates fusion-driven cytosolic entry, ensuring tumor-selective and efficient intracellular delivery. Nanogel@hMVs remain stable for 30 days, promote efficient uptake with minimal lysosomal sequestration, and silence Survivin. Across DNAzyme, siRNA, and ASO, they consistently produce potent gene silencing and in vitro antitumor activity. In vivo systemic administration yields preferential tumor accumulation, marked tumor inhibition, and prolonged survival without detectable toxicity. Collectively, Nanogel@hMVs establish a robust, safe, and adaptable lock-and-shield platform for systemic nucleic acid delivery in cancer therapy.
Insights
A novel lock-and-shield nanodelivery system protects nucleic acids for cancer gene therapy. This platform ensures efficient tumor cell delivery, potent gene silencing, and reduced toxicity, improving therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Effective cancer gene therapy faces challenges with nucleic acid delivery systems.
- Nucleic acids are susceptible to degradation and inefficient cellular uptake.
- Existing vectors exhibit limitations like cytotoxicity and poor tumor selectivity.
Purpose of the Study:
- To develop a robust and adaptable platform for systemic nucleic acid delivery in cancer therapy.
- To create a delivery system that protects nucleic acids and ensures efficient, tumor-selective intracellular release.
- To evaluate the efficacy and safety of the novel delivery system in preclinical cancer models.
Main Methods:
- Development of a lock-and-shield strategy using a hyaluronic acid Nanogel (Nanogel) with a hybrid membrane shell (hMVs), termed Nanogel@hMVs.
- Encapsulation of nucleic acids (DNAzyme, siRNA, ASO) within the Nanogel core with pH/redox-responsive linkers.
- Characterization of Nanogel@hMVs for stability, nucleic acid loading, cellular uptake, gene silencing, and in vitro/in vivo antitumor activity.
Main Results:
- Nanogel@hMVs demonstrated high nucleic acid entrapment efficiency (81.6%-89.2%) and 30-day stability.
- The system achieved efficient cellular uptake with minimal lysosomal sequestration and potent gene silencing (Survivin).
- In vivo studies showed preferential tumor accumulation, significant tumor inhibition, and prolonged survival with no detectable toxicity.
Conclusions:
- The Nanogel@hMVs platform offers a robust, safe, and adaptable solution for systemic nucleic acid delivery in cancer gene therapy.
- This lock-and-shield strategy overcomes key challenges in nucleic acid delivery, enhancing therapeutic potential.
- The system demonstrates broad applicability for various nucleic acid types and exhibits promising preclinical efficacy and safety.
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