Targeted Nucleic Acid Conjugates for Stable Cellular Delivery
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Solution Overview
Problem
Existing technologies face challenges in the targeted delivery of nucleic acids, such as oligonucleotides, with desirable pharmacokinetic properties for therapeutic applications, including improved targeting and slower degradation to enhance potency and reduce toxicity.
Innovation Solution
Conjugates are developed comprising targeting ligands like sugars or cell-penetrating peptides linked to nucleic acids or nanoparticles, utilizing click chemistry for assembly, to enhance delivery and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemical modifications with targeting moieties are made to nucleic acids, then targeting ability and in vivo stability are improved, but device complexity and manufacturing difficulty increase
Solution Approach 1:
The nucleic acid conjugate is divided into distinct functional segments: the nucleic acid payload, linker moieties, and targeting ligands. This segmentation allows each component to be optimized independently while maintaining overall functionality, resolving the contradiction between stability and complexity by organizing the complex structure into manageable, functionally-defined modules.
Solution Approach 2:
The invention creates composite nucleic acid conjugates by chemically linking nucleic acids with targeting ligands through linkers. This composite structure combines the stability and therapeutic function of nucleic acids with the targeted delivery capabilities of ligands like sugars or cell-penetrating peptides, achieving improved in vivo stability while managing complexity through systematic composite design.
2Reliability
If chemical modifications with targeting moieties are made to nucleic acids, then targeting ability is improved, but ease of manufacture decreases
Solution Approach 1:
The synthesis methodology employs preliminary protection of reactive groups on the nucleic acid and linking groups on the targeting ligand. This preliminary action prevents unwanted side reactions during conjugate formation and allows for cleaner, more efficient manufacturing. The protection strategies are designed to be removed under mild conditions after conjugation, facilitating easier manufacture while maintaining high targeting ability.
Solution Approach 2:
Linker moieties serve as intermediaries between the nucleic acid and targeting ligand. These linkers are designed with specific chemical functionalities that facilitate controlled conjugation reactions. The intermediary linkers enable modular assembly of the conjugate, improving ease of manufacture by allowing standardized linking protocols while preserving the targeting ability of the ligand through maintained spatial orientation and accessibility.
3Productivity
If higher dosing is used to achieve therapeutic effect, then efficacy is improved, but toxicity increases
Solution Approach 1:
The targeting ligands confer local quality enhancement to the nucleic acid conjugate, directing the therapeutic agent specifically to target cells or tissues. This localized delivery increases therapeutic efficacy at the target site while reducing exposure and toxicity in non-target tissues. The local quality modification through ligand attachment creates heterogeneity in the conjugate population, with each conjugate specifically oriented toward its target.
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 conjugates improve the delivery and efficacy of nucleic acids to target cells, allowing for lower dosing frequencies and improved toxicity profiles.
Implementation Method 1
utilizing click chemistry for assembly
Data Source
AI summary
Provided herein are conjugates comprising targeting moieties such as sugars, folates and cell-penetrating peptides, which can be used for the improved delivery of agents (e.g., nucleic acids, such as oligonucleotides or mRNAs, or other agents) to cells. The invention provides conjugates and compounds comprising targeting moieties, methods for preparing the same, and intermediates useful in their preparation. In another aspect, the present invention provides formulations (e.g., pharmaceutical compositions) comprising the targeting moiety-containing conjugates and compounds. The present invention also provides methods for delivering agents (e.g., nucleic acids such as oligonucleotides or mRNAs) to a cell, methods for treating and/or preventing a disease or condition in a subject, and methods for modulating gene expression in a cell or a subject. Further, provided herein are kits comprising the conjugates, or formulations thereof; and kits for the preparation of conjugates described herein.