Calcium-Salted Spherical Nucleic Acids for Stable Oligonucleotide Uptake

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Solution Overview

Problem

Therapeutic inhibitory oligonucleotides, such as siRNAs, face challenges with poor stability in the bloodstream and rapid clearance, limiting their effectiveness for systemic delivery due to inadequate cellular uptake and susceptibility to nuclease degradation.

Innovation Solution

Development of calcium chloride (CaCl2)-salted spherical nucleic acids (SNAs) with a nanoparticle core and a shell of oligonucleotides, where Ca2+ ions are adsorbed to the phosphate backbone, enhancing cellular uptake and resistance to nuclease degradation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If inhibitory oligonucleotides are used for therapeutic delivery, then gene regulation function is achieved, but cellular uptake is poor and stability in bloodstream is insufficient

Engineering Contradiction:

Improvegene regulation functionVSAvoidcellular uptake efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent embeds inhibitory oligonucleotides within a spherical nucleic acid structure consisting of a nanoparticle core nested within an oligonucleotide shell. This nested configuration protects the oligonucleotides from nuclease degradation while maintaining their gene regulation function, and the spherical structure facilitates cellular uptake through endocytosis.

Inventive Principle:

Principle #7Nested doll (Nesting)

Solution Approach 2:

The patent creates a composite spherical nucleic acid structure combining a nanoparticle core (made of materials like gold, silver, or polymer) with an oligonucleotide shell. This composite structure provides both the stability and cellular uptake properties needed for effective therapeutic delivery while maintaining the inhibitory function of the oligonucleotides.

Inventive Principle:

Principle #40Composite materials

2Reliability

If inhibitory oligonucleotides are administered systemically, then target gene modulation is achieved, but clearance from circulation is rapid

Engineering Contradiction:

Improvetarget gene modulationVSAvoidcirculation time

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent performs preliminary protection of the inhibitory oligonucleotides by embedding them within the spherical nucleic acid structure before administration. This pre-encapsulation protects the oligonucleotides from nuclease degradation in the bloodstream, extending their circulation time and ensuring they reach the target cells intact.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses an oligonucleotide shell as a protective flexible film surrounding the nanoparticle core. This shell structure protects the encapsulated oligonucleotides from degradation while allowing the spherical particle to circulate in the bloodstream and be taken up by target cells, thereby extending circulation time.

Inventive Principle:

Principle #30Flexible shells and thin films

3Productivity

If cationic polymers or peptides are used to enhance SNA uptake, then cellular uptake is improved, but cost increases and toxicity occurs

Engineering Contradiction:

Improvecellular uptakeVSAvoidcellular toxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent replaces expensive cationic polymers or peptides with calcium ions (Ca2+) as the salting agent. Calcium ions are inexpensive, naturally occurring divalent cations that can be easily introduced during the SNA formation process. They provide the necessary electrostatic interaction to enhance cellular uptake without the toxicity and cost issues associated with cationic polymers.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent changes the ionic composition parameter by using divalent calcium ions instead of monovalent sodium ions or cationic polymers. This parameter change in the salting condition modifies the electrostatic interactions at the SNA surface, enhancing cellular uptake through calcium-dependent endocytosis while avoiding the harmful effects of cationic polymers.

Inventive Principle:

Principle #35Parameter changes

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 CaCl2-salted SNAs demonstrate significantly improved gene regulation activity, up to 20-fold enhancement, with efficient cellular uptake and reduced nuclease sensitivity, facilitating targeted gene modulation and therapeutic applications.

Implementation Method 1

the SNA comprising Ca2+ ions adsorbed to the phosphate backbone of one or more oligonucleotides in the shell of oligonucleotides

Methodology Applied

Scientific EffectAdsorption: Adsorption

Data Source

PatentUS20250354140A1Calcium salted spherical nucleic acids

Publication Date: 2025.11.20 NORTHWESTERN UNIV

AI summary

The disclosure is generally related to calcium salted spherical nucleic acids (SNAs). SNAs comprise a nanoparticle core surrounded by a shell of oligonucleotides. In some aspects, the disclosure provides a spherical nucleic acid (SNA) comprising: (a) a nanoparticle core; and (b) a shell of oligonucleotides attached to the external surface of the nanoparticle core, wherein one or more oligonucleotides in the shell of oligonucleotides comprises a phosphate backbone; the SNA comprising Ca2+ ions adsorbed to the phosphate backbone of one or more oligonucleotides in the shell of oligonucleotides. Methods of making and using the SNAs are also provided herein.