One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus Dendrimer Delivery Systems for mRNA

Area of Science:

• Nanomedicine
• Drug Delivery Systems
• Biotechnology

Background:

• Efficient nucleic acid delivery is crucial for genetic nanomedicine, with viral and synthetic vectors like lipid nanoparticles (LNPs) being widely used for mRNA delivery.
• Current LNPs face challenges including limited stability, the 'PEG dilemma', and inefficient cargo encapsulation, hindering their therapeutic potential.

Purpose of the Study:

• To develop a novel, efficient, and stable one-component delivery system for messenger RNA (mRNA).
• To overcome the limitations associated with traditional four-component lipid nanoparticles (LNPs).

Main Methods:

• Synthesis of six libraries comprising 54 sequence-defined ionizable amphiphilic Janus dendrimers (IAJDs) using an accelerated modular-orthogonal methodology.
• Coassembly of IAJDs with mRNA into dendrimersome nanoparticles (DNPs) via a simple injection method, contrasting with LNP microfluidics.
• Evaluation of DNP activity and transfection efficiency in vitro and in vivo.

Main Results:

• 81% of synthesized IAJDs demonstrated in vitro activity, with 57% showing in vivo efficacy.
• Developed dendrimersome nanoparticles (DNPs) exhibit organ specificity and stability at 5 °C.
• Certain DNPs achieved higher transfection efficiency compared to positive controls both in vitro and in vivo.

Conclusions:

• The one-component multifunctional ionizable amphiphilic Janus dendrimer (IAJD) system offers a promising alternative to current mRNA delivery vectors.
• This proof-of-concept study provides insights into mRNA packaging and release mechanisms within dendrimersome nanoparticles (DNPs).
• IAJDs present a versatile platform for advancing genetic nanomedicine with improved efficiency and stability.