Branched Poly(beta-amino esters) for Nebulized mRNA Delivery
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Solution Overview
Problem
Current delivery systems for nucleic acids, such as mRNA, face challenges including toxicity, immunogenicity, and instability, particularly for non-viral delivery methods like nebulization, which are needed for therapeutic applications in lung epithelium and other tissues.
Innovation Solution
Development of poly(beta amino esters) (PBAE) polymers, specifically branched or hyperbranched structures, for stable formulations that can be used in nebulization or systemic administration, optimizing properties like solubility and transfection efficiency through controlled molecular weight and branching.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If branched polyethylenimine (bPEI) is used as a delivery vector, then transfection efficiency is improved, but toxicity increases due to accumulation of the polymer
Solution Approach 1:
The patent applies parameter changes by modifying the molecular weight of PEI polymers and controlling the degree of branching to optimize the balance between transfection efficiency and toxicity. Specifically, the invention uses PEI polymers with molecular weights below approximately 1.8 kDa with controlled branching degrees, which reduces toxicity while maintaining adequate transfection efficiency compared to conventional high molecular weight bPEI.
2Object-affected harmful factors
If lower molecular weight PEI is used, then toxicity is reduced, but transfection efficiency is diminished
Solution Approach 1:
The patent employs composite materials by creating branched or hyperbranched PEI structures with specific molecular weights and branching degrees. This composite approach combines the low toxicity advantage of low molecular weight PEI with the enhanced transfection efficiency typically associated with branching, achieving a synergistic effect that resolves the contradiction between toxicity reduction and transfection maintenance.
Solution Approach 2:
The invention systematically varies the molecular weight parameter (keeping it below 1.8 kDa) and the degree of branching parameter to find the optimal combination that maintains transfection efficiency while minimizing toxicity. This parametric optimization allows the polymer to effectively deliver nucleic acids without causing excessive cellular damage.
3Productivity
If DNA is used for gene therapy, then gene delivery is achieved, but insertional mutagenesis risk increases
Solution Approach 1:
The patent extracts the problematic integration step from the gene delivery process by using mRNA instead of DNA. This extraction eliminates the risk of insertional mutagenesis entirely, as mRNA delivers genetic information temporarily without integrating into the host genome, while still achieving the therapeutic goal of protein expression in lung epithelium cells.
4Productivity
If invasive intra-tracheal delivery is used for mRNA, then transfection efficiency is improved, but delivery complexity and patient burden increase
Solution Approach 1:
The patent introduces an intermediary delivery system using nebulized aerosols that mediate between the mRNA therapeutic agent and the lung epithelium target cells. This intermediary approach enables non-invasive delivery through the respiratory tract, simplifying the administration process while maintaining effective transfection through the use of optimized PEI polymers as transfection mediators.
Data Source
AI summary
Provided herein are branched poly(beta-amino esters) (PBAE) useful as vehicles for the delivery of therapeutic agents, such as nucleic acids. The disclosed polymers form stable compositions, and are suitable for the delivery of therapeutic agents via nebulization. Compositions of the disclosed polymers are capable of delivering therapeutic agents such as mRNA to lung epithelial cells.