Harnessing pH-Sensitive Polycation Vehicles for the Efficient siRNA Delivery.

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery Systems

Background:

• Amphiphilic polycation vehicles show promise for siRNA delivery, facilitated by pH-sensitive hydrophobic segments.
• Optimal design principles for these vehicles to maximize siRNA delivery efficiency remain incompletely understood.

Purpose of the Study:

• To elucidate a multifactor matching concept for designing efficient amphiphilic polycation vehicles for siRNA delivery.
• To investigate the influence of pKa values, proton buffering capacities (BCs), and critical micelle concentrations (CMCs) on vehicle performance.

Main Methods:

• Synthesis and characterization of a library of amphiphilic polycations: mPEG-PAMA50-P(DEA-r-D5A) (EAE5).
• Evaluation of siRNA delivery efficiency in vitro and in vivo across different EAE5 formulations.
• Correlation of physicochemical properties (pKa, BCs, CMC) with gene knockdown efficacy and therapeutic outcomes.

Main Results:

• Stronger BCs in the pH 5.5-7.4 range, induced by EAE548/29 and EAE539/37, enhanced in vitro siRNA delivery.
• EAE539/37 demonstrated superior in vivo siRNA delivery via intravenous and subcutaneous routes, attributed to BCs in pH 5.5-6.5 and lower CMC.
• EAE539/37 achieved 87.2% gene knockdown via subcutaneous injection, showing potential as an mRNA vaccine adjuvant and effective tumor delivery for antitumor activity.

Conclusions:

• A multifactor matching concept involving suitable pKa, strong BCs within pH 5.5-6.5, and low CMCs is crucial for designing efficient polycationic siRNA delivery vehicles.
• EAE539/37 represents a promising candidate for advanced siRNA delivery applications, including potential mRNA vaccine adjuvant and cancer therapy.