Adapter-Mediated Cell Penetrating Peptide Delivery

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Solution Overview

Problem

Cell-penetrating peptides (CPPs) face limitations in penetration efficiency and endosomal entrapment, preventing their broad adoption for altering the intracellular environment due to high affinity interactions with receptors, leading to trapped cargo proteins and potential hazards in eukaryotic expression.

Innovation Solution

A composition comprising a cell-penetrating peptide (CPP) covalently linked to an adapter, with a cargo molecule linked to an adapter binding molecule, forming a non-covalent linkage that reverses in an intracellular environment, such as low calcium concentrations, allowing for efficient release of the cargo from endosomes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CPPs are used to deliver cargo molecules into cells, then intracellular delivery is achieved, but cargo molecules become trapped in endosomes due to high affinity interactions with receptors

Engineering Contradiction:

Improveintracellular delivery efficiencyVSAvoidcargo release from endosomes

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent introduces an adapter molecule as an intermediary between the CPP and the cargo. The adapter binds to the CPP with high affinity to facilitate cellular uptake, then undergoes conformational change or cleavage in the endosomal environment to release the cargo, solving the entrapment problem without sacrificing delivery efficiency

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The adapter molecule exhibits dynamic behavior - it maintains a stable binding conformation during cellular uptake but undergoes conformational change or cleavage in response to endosomal conditions (such as low pH or specific enzymes), enabling cargo release at the target location

Inventive Principle:

Principle #15Dynamics

2Productivity

If CPPs are covalently linked to cargo molecules, then penetration efficiency is improved, but cytotoxicity and handling complexities increase

Engineering Contradiction:

Improvepenetration efficiencyVSAvoidcytotoxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the CPP-cargo conjugate into three separate components: the CPP, the adapter, and the cargo. The CPP and cargo remain separate entities that only interact transiently during the delivery process, reducing cytotoxicity while maintaining penetration efficiency through the adapter-mediated mechanism

Inventive Principle:

Principle #1Segmentation

3Quantity of substance

If CPPs are used for intracellular delivery, then cargo transport across plasma membrane is achieved, but endosomal entrapment prevents efficient release into cytoplasm

Engineering Contradiction:

Improvecargo transport across membraneVSAvoidcargo release into cytoplasm

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The adapter is pre-designed with conditional stability features that allow it to protect the cargo during uptake but automatically release it under endosomal conditions. This preliminary design ensures that cargo release is triggered automatically upon reaching the endosome, without requiring additional intervention

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS11192922B2Signal molecules as cell penetration agents

Publication Date: 2021.12.07 KENNESAW STATE UNIV RES & SERVICE FOUND

AI summary

Novel cell penetrating agents for intracellular delivery of desired cargo, including proteins. Use of cell penetrating agents to deliver cargos to the interior of cells and cellular compartments and organelles is transformative for diagnostic, therapeutic, and research processes.