Exosome-ASO Delivery for Targeted CEBP/β Silencing in Myeloid Cells
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Solution Overview
Problem
Existing drug delivery methods, particularly those using exosomes, face challenges in stability and targeting of antisense oligonucleotides (ASOs) in vivo, limiting their effectiveness in regulating gene expression for therapeutic applications, especially in reducing CEBP/β expression in myeloid-derived suppressor cells (MDSCs) and other myeloid cells.
Innovation Solution
Development of extracellular vesicles, such as exosomes, engineered to carry ASOs that are complementary to specific sequences in the CEBP/β transcript, enabling targeted delivery to MDSCs and other myeloid cells, thereby down-regulating CEBP/β expression and promoting immune modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional drug delivery methods are used to deliver ASOs, then the ASOs can reach target cells, but the stability and targeting efficiency of ASOs in vivo is insufficient
Solution Approach 1:
The patent uses exosomes as intermediary carriers to deliver ASOs to target cells. The exosome membrane protects the ASO payload from degradation in vivo while enabling targeted delivery to myeloid-derived suppressor cells and other myeloid cells through natural homing capabilities and surface marker recognition.
Solution Approach 2:
The invention creates a composite delivery system combining exosomal membranes with encapsulated ASO molecules. This composite structure integrates the protective and targeting properties of exosomes with the gene-regulating function of ASOs, achieving both stability and effectiveness.
2Ease of manufacture
If ASOs are delivered without targeted vesicles, then delivery is simpler, but the down-regulation of CEBP/β expression in specific myeloid cells is insufficient
Solution Approach 1:
The exosomes used in this invention possess natural self-targeting capabilities through their surface markers and homing properties. They automatically navigate to and are taken up by myeloid-derived suppressor cells and other myeloid cells without requiring complex external targeting modifications, thereby maintaining ease of manufacture while achieving precise cellular targeting.
3Reliability
If exosomes are engineered to carry ASOs, then targeted delivery to myeloid cells is achieved, but the complexity of the delivery system increases
Solution Approach 1:
The invention applies local quality modification by engineering specific surface markers or ligands on the exosome membrane at localized regions to enhance targeting to myeloid cells, while keeping the rest of the exosome structure and composition relatively simple and natural. This allows targeted delivery without requiring complete reconstruction of the exosome system.
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 engineered exosomes effectively reduce CEBP/β protein and mRNA expression in immune cells by up to 100%, enhancing immune modulation and providing a potent therapeutic approach for conditions like cancer and inflammation.
Implementation Method 1
the ASO comprises a contiguous nucleotide sequence that is complementary to a nucleic acid sequence within a CEBP/β transcript
Data Source
AI summary
The present disclosure relates to extracellular vesicles, e.g., exosomes, comprising an antisense oligonucleotide (ASO), wherein the ASO comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to a nucleic acid sequence within a CEBP/β transcript. Also provided herein are methods for producing the exosomes and methods for using the exosomes to treat and/or prevent diseases or disorders.