Charge-Protected Pro-Oligos for Efficient RNAi Delivery
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Solution Overview
Problem
Current methods for delivering biomolecules, particularly negatively charged molecules like polynucleotides, face challenges such as limited cell infectivity, immune responses, cytotoxicity, and inefficiency in large-scale production, especially with viral-based and cationic liposome systems.
Innovation Solution
Development of compounds acting as protecting groups that reversibly mask the negative charge of biomolecules, enhancing their lipophilicity and facilitating delivery across cell membranes by being biolabile and linked via covalent or non-covalent bonds, allowing for intracellular release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If cationic liposomes are used for delivery, then delivery efficiency is improved, but cytotoxicity increases
Solution Approach 1:
The patent modifies the charge parameter of the delivery system by using neutral or anionic liposomes instead of cationic liposomes, thereby reducing cytotoxicity while maintaining delivery efficiency through alternative mechanisms such as targeted ligand attachment and endosomal escape pathways
Solution Approach 2:
The patent introduces targeting ligands (antibodies, peptides, or other recognition molecules) as intermediaries that mediate the interaction between the liposome and target cells, enabling specific delivery without relying on electrostatic attraction, thus reducing cytotoxicity while improving delivery efficiency
2Productivity
If viral-based delivery systems are used, then delivery efficiency is improved, but immune responses and production difficulty increase
Solution Approach 1:
The patent employs non-viral liposomal vectors that are simpler to produce and dispose of, replacing complex viral vectors with readily manufacturable lipid-based systems that achieve comparable delivery efficiency through chemical rather than biological mechanisms
Solution Approach 2:
The patent creates composite liposomal structures combining lipids with targeting ligands, protective coatings, and therapeutic payloads, achieving viral-level delivery efficiency through carefully engineered material compositions without the complexities of viral assembly
3Reliability
If negatively charged biomolecules are delivered, then therapeutic effect is improved, but cell membrane penetration becomes difficult
Solution Approach 1:
The patent uses liposomal membranes and targeting ligands as intermediaries that facilitate the passage of negatively charged biomolecules across the cell membrane through endocytosis and endosomal escape mechanisms, overcoming the electrostatic repulsion barrier
Solution Approach 2:
The patent modifies the delivery system's charge parameters by using neutral or anionic liposomes that can approach and interact with cell membranes without electrostatic repulsion, then utilize pH-dependent or other environmental triggers to release the negatively charged therapeutic payload inside 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
The solution enables efficient and reduced cytotoxic delivery of biomolecules, achieving high knockdown efficacy and stability with minimal reversal toxicity, as demonstrated by significant reduction in gene expression in cellular models.
Implementation Method 1
compounds acting as protecting groups that reversibly mask the negative charge of biomolecules, enhancing their lipophilicity
Implementation Method 2
enhancing their lipophilicity and facilitating delivery across cell membranes
Implementation Method 3
linked via covalent or non-covalent bonds, allowing for intracellular release
Data Source
AI summary
Disclosed herein are compositions and methods for generating ribo-nucleic neutral (RNN) or deoxyribo-nucleic-neutral (DNN) polynucleotides with reduced anionic charge, for improved intracellular delivery. Also disclosed herein are methods of using RNN and DNN compositions.