TLR9-Targeted Spherical Nucleic Acids for Reduced Off-Target Toxicity

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Solution Overview

Problem

Existing TLR 7/8 and 9 agonists face efficacy issues, off-target phosphorothioate effects, and toxicity concerns, limiting their clinical translation for treating intracellular pathogens and cancers.

Innovation Solution

Development of immunostimulatory spherical nucleic acids (IS-SNAs) comprising a core with immunostimulatory oligonucleotides and a checkpoint inhibitor, which can be administered intravenously, subcutaneously, or intratumorally, to induce potent TH1-type cytokine secretion and enhance T-effector cell activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If TLR 7/8 and 9 agonists are used to induce immune responses, then the ability to clear intracellular pathogens and cancers is improved, but off-target phosphorothioate effects and toxicity occur

Engineering Contradiction:

Improveefficacy in clearing intracellular pathogens and cancersVSAvoidoff-target phosphorothioate effects and toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The spherical nucleic acid structure segments the immunostimulatory oligonucleotides into discrete radial positions around a core, with each oligonucleotide independently oriented to present immunostimulatory sequences while minimizing off-target effects through spatial separation and controlled presentation

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The oligonucleotides are positioned with specific local orientations on the spherical surface, creating regions of high immunostimulatory activity at the exterior while the core provides structural support and controlled release properties, achieving localized therapeutic effect with reduced systemic toxicity

Inventive Principle:

Principle #3Local quality

2Reliability

If immunostimulatory oligonucleotides are administered to induce TH1-type cytokine secretion, then T-effector cell activity is enhanced, but off-target effects occur

Engineering Contradiction:

ImproveTH1-type cytokine secretion and T-effector cell activityVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The spherical nucleic acid structure acts as an intermediary carrier that presents immunostimulatory oligonucleotides in a controlled manner, mediating the interaction between the oligonucleotides and immune cells while reducing direct off-target effects through the spherical architecture and controlled presentation surface

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The spherical nucleic acid combines immunostimulatory oligonucleotides with a core structure (such as lipid or polymer) to create a composite material that enhances therapeutic efficacy through synergistic effects while the core provides biocompatibility and reduced toxicity

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS20250304974A1TLR9-targeted spherical nucleic acids having potent antitumor activity

Publication Date: 2025.10.02 FLASHPOINT THERAPEUTICS INC

AI summary

Aspects of the invention relate to immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of a disorder, such as cancer. The IS-SNA may be administered together with a checkpoint inhibitor.