Base-Modified RNA Nanostructures for Lower Innate Immunogenicity

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Solution Overview

Problem

RNA nanostructures trigger strong innate immune responses due to recognition by pattern recognition receptors, potentially compromising therapeutic efficacy and causing cell apoptosis or necroptosis.

Innovation Solution

Incorporation of base modifications such as 5-methylcytosine (m5C), pseudouridine (ψ), and N1-methylpseudouridine (m1ψ) during in vitro transcription to reduce immunogenicity, allowing RNA nanostructures to retain their geometrical configurations while being less recognized by innate immune sensors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If base modifications (m5C, ψ, m1ψ) are incorporated into RNA nanostructures during in vitro transcription, then innate immunogenicity is significantly reduced, but the complexity of the synthesis process increases

Engineering Contradiction:

Improveinnate immunogenicityVSAvoidsynthesis process complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by incorporating modified nucleotide triphosphates (m5C-CTP, ψ-UTP, m1ψ-UTP) during the in vitro transcription process. These chemical modifications alter the RNA's interaction with innate immune sensors, changing the immunogenicity parameter while maintaining the RNA nanostructure's functional properties

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The base modifications are introduced during the synthesis stage (in vitro transcription) before the RNA nanostructure is deployed therapeutically. This preliminary action pre-empts immune recognition by modifying the RNA sequence to avoid activation of pattern recognition receptors, thereby reducing immunogenicity before therapeutic use

Inventive Principle:

Principle #10Preliminary action

2Reliability

If base modifications are incorporated to reduce immunogenicity, then biocompatibility is enhanced, but manufacturing precision requirements increase

Engineering Contradiction:

ImprovebiocompatibilityVSAvoidmodification incorporation precision

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent utilizes parameter changes by incorporating specific modified nucleotide triphosphates (m5C-CTP, ψ-UTP, m1ψ-UTP) at defined positions during in vitro transcription. These modifications alter the RNA's molecular properties to reduce recognition by innate immune sensors, thereby enhancing biocompatibility while requiring precise control over modification incorporation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The in vitro transcription system acts as an intermediary that incorporates modified nucleotide triphosphates into the RNA strand. This intermediary process allows precise control over where and how modifications are introduced, enabling high manufacturing precision in the placement of immune-evasive modifications

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If base modifications are used to reduce immune recognition, then therapeutic efficacy is improved, but the cost of production increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidproduction cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by incorporating modified nucleotide triphosphates (m5C-CTP, ψ-UTP, m1ψ-UTP) during in vitro transcription. These modifications reduce immune recognition and enhance therapeutic efficacy, though they do increase production costs due to the specialized nature of the modified nucleotides

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The modifications are introduced during the synthesis stage (in vitro transcription) before therapeutic deployment. This preliminary incorporation of immune-evasive modifications ensures therapeutic efficacy is enhanced from the outset, avoiding the need for additional post-production modifications or corrective measures

Inventive Principle:

Principle #10Preliminary action

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

Significantly reduces innate immune responses, enhances biocompatibility, and increases thermal stability of RNA nanostructures, making them safer and more effective for therapeutic applications.

Implementation Method 1

Incorporation of base modifications such as 5-methylcytosine (m5C), pseudouridine (ψ), and N1-methylpseudouridine (m1ψ) during in vitro transcription to reduce immunogenicity

Methodology Applied

Scientific EffectBase modification:

Implementation Method 2

the RNA strand is configured to self-assemble into the RNA nanostructure

Methodology Applied

Scientific EffectSelf-assembly: Self-Assembly

Implementation Method 3

SQs with m5C and/or ψ/m1ψ modifications were successfully synthesized by in vitro transcription, and the shapes were not obviously altered by the modifications

Methodology Applied

Scientific EffectCohesion: Cohesion

Data Source

PatentUS20260028622A1RNA nanostructures with base modifications for reducing innate immunogenicity

Publication Date: 2026.01.29 THE ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIV OF ARIZONA

AI summary

RNA nanostructures with significantly reduced immunogenicity are described herein, enhancing their therapeutic utility. Incorporating specific base modifications during in vitro transcription decreases recognition by innate immune sensors. This breakthrough enables safer and more effective applications in targeted drug delivery and gene therapy, representing a significant advancement over current RNA-based technologies.