pH-Sensitive Immolative Polymer for Nucleic Acid Delivery
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Solution Overview
Problem
There is a need for new materials and strategies to effectively deliver therapeutic agents, diagnostic probes, and research tools across cell membranes and biological barriers for various clinical and research applications, particularly for nucleic acids in vaccination strategies, cancer immunotherapy, and gene editing.
Innovation Solution
A cell-penetrating complex comprising a nucleic acid non-covalently bound to a cationic amphipathic polymer with a pH-sensitive imidolation domain and a lipophilic polymer domain, which facilitates the transport of nucleic acids across cellular membranes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If nucleic acids are delivered across cell membranes using conventional methods, then delivery efficiency is improved, but cellular toxicity increases
Solution Approach 1:
The polymer undergoes pH-dependent conformational changes and degradation. At acidic endosomal pH, the polymer degrades to release nucleic acids, while at physiological pH it maintains a stable complex structure. This dynamic parameter change enables efficient delivery with reduced toxicity.
Solution Approach 2:
The system uses a composite structure combining cationic polymer and nucleic acid to form cell-penetrating complexes. The cationic nature facilitates membrane interaction while the overall composite structure controls toxicity and enables cellular uptake.
2Productivity
If cationic polymers are used to enhance nucleic acid binding and cellular uptake, then transfection efficiency is improved, but cytotoxicity increases
Solution Approach 1:
The polymer is designed with pH-sensitive bonds that cause it to degrade at endosomal pH levels, releasing the nucleic acid cargo while the polymer itself breaks down into less toxic components, thereby reducing cytotoxicity after delivering its function.
Solution Approach 2:
The polymer acts as a disposable delivery vehicle that performs its function of binding and delivering nucleic acids, then degrades completely after use, eliminating persistent toxic effects from the polymer itself.
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 complex enables efficient and effective delivery of nucleic acids into cells, demonstrating superior transfection efficiency and safety in various cell types and tissues, including reticulocytes and hematopoietic stem cells, with minimal toxicity.
Implementation Method 1
a cell-penetrating complex comprising a nucleic acid non-covalently bound to a cationic amphipathic polymer
Implementation Method 2
the cationic amphipathic polymer including a pH-sensitive immolation domain
Data Source
AI summary
There are provided herein, inter alia, complexes, compositions and methods for the delivery of therapeutic, diagnostic and imaging agents, including nucleic acid, into a cell. The complexes, compositions and methods may facilitate complexation, protection, delivery and release of oligonucleotides and polyanionic cargos into lung cells and lung tissue, both in vitro and in vivo.