Transiently Protected Polynucleotides for Cytotoxicity-Free Delivery
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Solution Overview
Problem
Current methods for delivering polynucleotides, such as siRNAs, face challenges due to their anionic charge and large size, which hinder cellular uptake, and often result in cytotoxicity when using cationic lipids as delivery agents, especially for primary cells and hematopoietic cell lineages.
Innovation Solution
Development of transiently protected polynucleotides with anionic charge-neutralizing moieties that can enter cells via endocytic or macropinocytic mechanisms, featuring bioreversible groups that are cleaved intracellularly, allowing for the attachment of auxiliary moieties like peptides, polymers, or therapeutic agents, facilitating intracellular delivery without the need for toxic carriers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If cationic lipids are used to deliver polynucleotides, then cellular uptake is improved, but cytotoxicity increases
Solution Approach 1:
The patent extracts the harmful cationic lipid carrier from the delivery system and replaces it with a biodegradable polymer carrier that does not cause cytotoxicity. The polynucleotide is conjugated to a biodegradable polymer through a cleavable linkage, eliminating the need for toxic cationic lipids while maintaining delivery functionality.
Solution Approach 2:
The patent changes the chemical composition parameters of the delivery carrier from cationic lipids to biodegradable polymers with specific molecular weight ranges (10,000-1,000,000 Da). This parameter change maintains the ability to facilitate cellular uptake while eliminating cytotoxic effects associated with traditional cationic lipid carriers.
2Stability of the object's composition
If polynucleotides are made larger to improve stability, then structural integrity is improved, but cellular uptake decreases
Solution Approach 1:
The patent introduces a biodegradable polymer as an intermediary carrier that conjugates to the polynucleotide. This intermediary complex allows the polynucleotide to maintain its structural integrity while the polymer carrier facilitates cellular uptake through endocytic mechanisms, solving the size-related uptake problem.
Solution Approach 2:
The patent creates a composite delivery system combining biodegradable polymer and polynucleotide components. The composite structure leverages the stability of the polynucleotide and the cellular uptake capabilities of the polymer carrier, achieving both structural integrity and efficient delivery.
3Productivity
If polynucleotides are conjugated to carriers to improve delivery, then cellular uptake is improved, but device complexity increases
Solution Approach 1:
The patent segments the delivery system into distinct modular components: the polynucleotide payload and the biodegradable polymer carrier. This segmentation allows for independent optimization of each component and simplifies the conjugation process through defined cleavable linkages, reducing overall system complexity.
Solution Approach 2:
The patent employs a biodegradable polymer carrier that is designed to be temporarily present in the cell and then degraded. This disposable-like approach eliminates the need for complex retrieval mechanisms, simplifying the delivery system while ensuring the carrier does not persist harmfully in the cell.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enhances cellular uptake and reduces cytotoxicity, enabling effective delivery of polynucleotides for therapeutic, diagnostic, and research applications by neutralizing the anionic charge and allowing for intracellular action without the use of cationic lipids.
Implementation Method 1
transiently protected polynucleotides comprising an anionic charge-neutralizing moiety/group
Implementation Method 2
once inside a cell, it is designed to be removed by enzymatic activity or by passive intracellular methods
Implementation Method 3
bioreversible groups that are cleaved intracellularly
Implementation Method 4
These compounds can enter the cytosol of cells by endocytic or macropinocytic mechanisms
Data Source
AI summary
The disclosure provides methods and compositions for delivering polynucleotides into cells. The disclosure provides transiently protected polynucleotides comprising an anionic charge-neutralizing moiety/group, which may also confer additional functionality. These compounds can enter the cytosol of cells by endocytic or macropinocytic mechanisms. The transient protecting group is bioreversible, i.e., once inside a cell, it is designed to be removed by enzymatic activity or by passive intracellular methods (e.g., changes in pH or reductive environment).