Peptide-Displayed Nuclease for Tumor Tissue Diffusion

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Solution Overview

Problem

Existing gene editing platforms using CRISPR nucleases are limited by size, which impedes diffusion in biological tissues, particularly in the core of tumors, affecting bioavailability and delivery efficiency.

Innovation Solution

A polynucleotide-modifying enzyme (PNME) with a functional nuclease domain and a display domain comprising a peptidic recognition sequence that targets cell receptors, allowing cell internalization, is developed. This enzyme is designed to minimize size by eliminating the need for additional cell recognition domains, enhancing bioavailability and diffusion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If a receptor binding domain (Nab) is added to CRISPR nuclease for cell targeting, then cell recognition and internalization capability is improved, but the overall molecular weight and hydrodynamic radius increase, reducing diffusion capability in biological tissues

Engineering Contradiction:

Improvecell recognition capabilityVSAvoidhydrodynamic radius

Core Design Contradiction:

Adaptability or versatilityVSLength of moving object

Solution Approach 1:

The invention extracts only the essential peptidic recognition sequence (3-20 amino acids) from complete immunoglobulin domains or nanobodies, retaining cell targeting functionality while removing unnecessary structural elements that contribute to size. This extracted peptide sequence is sufficient for receptor binding and cell internalization without the bulk of the full immunoglobulin structure.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention replaces large, complex immunoglobulin domains with small, simple peptidic recognition sequences that are minimally sufficient for the intended function. These short peptide sequences serve as disposable, functionally adequate alternatives to bulky protein domains, achieving the same cell targeting effect with dramatically reduced molecular weight.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Weight of moving object

If the size of gene editing platform is reduced by using smaller immunoglobulin mimetics, then molecular weight is decreased, but diffusion capability in tissues remains insufficient due to large hydrodynamic radius

Engineering Contradiction:

Improvemolecular weightVSAvoiddiffusion capability

Core Design Contradiction:

Weight of moving objectVSSpeed

Solution Approach 1:

The invention extracts only the critical peptidic recognition sequence from immunoglobulin structures, eliminating the hydrophobic core and framework regions that contribute to large hydrodynamic radius. This leaves only the minimal peptide sequence needed for receptor interaction, optimizing both weight and diffusion properties.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the physical parameters of the recognition domain from large protein structures (immunoglobulins, nanobodies) to small peptide sequences, fundamentally altering the molecular weight and hydrodynamic radius parameters to achieve optimal diffusion characteristics in biological tissues.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If CRISPR nuclease is used for gene editing, then programmability and design speed are improved, but the size of the nuclease complex is large, limiting tissue penetration and bioavailability

Engineering Contradiction:

Improvedesign speedVSAvoidnuclease complex size

Core Design Contradiction:

ProductivityVSWeight of moving object

Solution Approach 1:

The invention extracts and optimizes the recognition domain to minimal peptidic sequences, reducing the overall complex size while preserving the CRISPR nuclease's programmable gene editing functionality. This extraction of essential elements maintains design speed advantages while improving delivery characteristics.

Inventive Principle:

Principle #2Taking out (Extraction)

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 PNME achieves improved bioavailability and enhanced diffusion in tissues, particularly targeting tumor cells, with reduced size and increased efficiency in gene editing capabilities.

Implementation Method 1

said peptidic recognition sequence recognizes a target cell receptor of a target cell to allow cell internalization of the polynucleotide-modifying enzyme in said target cell

Methodology Applied

Scientific EffectReceptor recognition and binding: Absorption (physical)

Implementation Method 2

The size may limit the ability to diffuse in biological tissues, for example into the core of a tumour

Methodology Applied

Scientific EffectDiffusion: Diffusion

Data Source

PatentUS20260055388A1A polynucleotide-modifying enzyme comprising a peptidic recognition sequence

Publication Date: 2026.02.26 JENTHERA THERAPEUTICS INC

AI summary

There is provided a polynucleotide-modifying enzyme with a functional nuclease domain and a display domain. The functional nuclease domain comprises a nuclease catalytic pocket. The display domain comprises a peptidic recognition sequence of from 3 to 20 amino acids in length, in a loop, an alpha helix or an extension off the end of the alpha helix that is positioned on an external surface of the polynucleotide-modifying enzyme. The peptidic recognition sequence recognizes a target cell receptor of a target cell to allow cell internalization of the polynucleotide-modifying enzyme in said target cell.