Effective systemic siRNA delivery using dual-layer protected long-circulating nanohydrogel containing an inorganic...

Area of Science:

• Biomaterials Science
• Nanotechnology
• Gene Therapy

Background:

• Systemic delivery of small interfering RNA (siRNA) faces challenges including enzymatic degradation and poor cellular uptake.
• Calcium phosphate (CaP) offers biocompatibility and siRNA entrapment but requires surface modification for improved systemic delivery.
• Developing effective carriers is crucial for advancing siRNA-based therapeutics.

Purpose of the Study:

• To engineer a novel nanohydrogel system for enhanced systemic delivery of siRNA.
• To improve the stability, circulation time, and tumor-specific distribution of siRNA.
• To evaluate the therapeutic efficacy of the developed system in inhibiting tumor growth via VEGF gene silencing.

Main Methods:

• Fabrication of a CaP/siRNA core.
• Surface modification with dual hydrogel layers of dextran and polyethylene glycol (PEG) conjugated with 3,4-dihydroxy-l-phenylalanine (dopa) (PEG-dex-dopa).
• In vivo evaluation of pharmacokinetic behavior, tumor distribution, and anti-tumor efficacy, including VEGF gene expression analysis.

Main Results:

• The PEG-dex-dopa/CaP/siRNA nanohydrogel demonstrated controlled overgrowth and stabilization of the CaP/siRNA core.
• The dual hydrophilic layers significantly improved siRNA pharmacokinetics, reducing hepatic accumulation and systemic clearance.
• Enhanced siRNA distribution to tumors was observed, leading to effective tumor growth inhibition through VEGF gene silencing via the EPR effect.

Conclusions:

• The PEG-dex-dopa nanohydrogel provides a promising platform for overcoming siRNA delivery barriers.
• This system enhances systemic siRNA delivery, improves tumor targeting, and achieves significant anti-tumor effects.
• The developed nanohydrogel holds potential for advanced cancer gene therapy applications.