Biodegradable PBAE Nanoparticles for SAM Delivery

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Solution Overview

Problem

Self-amplifying mRNA (SAM) vaccines face challenges in achieving effective cytosolic delivery due to mRNA susceptibility to nuclease damage, and existing delivery platforms like lipid nanoparticles have drawbacks such as cold storage requirements and potential for inducing inflammation.

Innovation Solution

Development of biodegradable poly(beta-amino ester) (PBAE) nanoparticles that encapsulate SAM, utilizing alkyl-amine side chains and PEGylation to enhance stability and delivery efficacy, allowing for efficient intramuscular delivery and induction of robust immune responses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If lipid nanoparticles are used for SAM delivery, then delivery efficacy is improved, but cold storage requirements and potential for inducing inflammation occur

Engineering Contradiction:

Improvedelivery efficacyVSAvoidcold storage requirements and inflammation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical composition parameters of the nanoparticle by using poly(beta-amino ester) polymers with specific molecular weights (5-50 kDa) and incorporating alkyl-amine side chains, replacing the lipid-based formulation. This parameter change eliminates cold storage requirements and reduces inflammation while maintaining delivery efficacy.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite nanoparticle system combining poly(beta-amino ester) polymer backbone with alkyl-amine side chains and amine-containing end capping groups. This composite structure provides both the protective encapsulation needed for SAM delivery and the biodegradability to avoid chronic inflammation, resolving the contradiction between delivery efficacy and harmful effects.

Inventive Principle:

Principle #40Composite materials

2Reliability

If polymeric dendrimers are used for SAM delivery, then delivery capability is improved, but slow degradability and induction of inflammation occur

Engineering Contradiction:

Improvedelivery capabilityVSAvoiddegradability

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent optimizes the polymer molecular weight parameter to 5-50 kDa, which is specifically tuned to provide adequate delivery capability while ensuring rapid enough degradation to avoid chronic inflammation. This parameter optimization resolves the contradiction between delivery capability and degradability.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs biodegradable poly(beta-amino ester) polymers that are designed to be transient in the body, degrading into harmless metabolites. This approach uses a short-living carrier that fulfills its delivery function and then disappears, avoiding the accumulation and chronic inflammation associated with non-degradable materials.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Ease of operation

If naked SAM is administered, then simplicity of administration is maintained, but nuclease damage and elimination of self-amplification ability occur

Engineering Contradiction:

Improvesimplicity of administrationVSAvoidresistance to nuclease damage

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent introduces poly(beta-amino ester) nanoparticles as an intermediary carrier that encapsulates the SAM. This intermediary protects the SAM from nucleases in the extracellular space while still allowing the SAM to reach the cytosol and perform its function, thus resolving the contradiction between administration simplicity and nuclease resistance.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent uses a flexible polymeric nanoparticle shell that encapsulates the SAM. This shell is thin enough to allow molecular interactions but protective enough to shield against nucleases. The flexible polymer structure adapts to the SAM and provides continuous protection during circulation and cellular uptake.

Inventive Principle:

Principle #30Flexible shells and thin films

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 PBAE nanoparticles achieve up to 37-fold higher expression of SAM in muscle tissue compared to naked SAM, eliciting protective immunity at low doses and improving immunogenicity, with potential for next-generation mRNA-based vaccines.

Implementation Method 1

biodegradable poly(beta-amino ester) (PBAE) nanoparticles that encapsulate SAM

Methodology Applied

Scientific EffectElectrostatic interaction: Electrostatics

Implementation Method 2

utilizing alkyl-amine side chains and PEGylation to enhance stability and delivery efficacy

Methodology Applied

Scientific EffectPEGylation:

Implementation Method 3

allowing for efficient intramuscular delivery and induction of robust immune responses

Methodology Applied

Scientific EffectImmune response induction:

Data Source

PatentUS20250017866A1Polymers and nanoparticles for intramuscular nucleic acid delivery

Publication Date: 2025.01.16 JOHNS HOPKINS UNIVERSITY

AI summary

Biodegradable cationic polyesters for intramuscular delivery of nucleic acids, including self-amplifying mRNA, and methods of their use for treating conditions or diseases are disclosed.