pH-Responsive Phospholipid for mRNA Delivery With Lower Cytotoxicity
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Solution Overview
Problem
Existing delivery systems for medicinal substances like mRNA face challenges due to rapid degradation by nucleases and poor membrane penetration, and positively charged lipids used for encapsulation raise cytotoxicity concerns.
Innovation Solution
A pH-responsive phospholipid represented by formula (1) forms lipid particles that are not positively charged at neutral pH, enabling efficient encapsulation and delivery of medicinal substances, particularly mRNA, while reducing cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a positively charged lipid is used for encapsulation, then electrostatic interaction with negatively charged nucleic acid is improved, but cytotoxicity increases
Solution Approach 1:
The phospholipid's charge state is changed by adjusting the pH of the surrounding environment. At acidic pH (endosome/lysosome), the phospholipid becomes positively charged to facilitate nucleic acid encapsulation. At neutral pH (cytoplasm/extracellular), the phospholipid becomes negatively charged to reduce cytotoxicity. This dynamic charge adjustment resolves the contradiction between encapsulation efficiency and cytotoxicity.
2Reliability
If a lipid particle is designed for efficient encapsulation, then medicinal substance delivery is improved, but membrane penetration ability deteriorates
Solution Approach 1:
The phospholipid particle dynamically adjusts its surface charge properties in response to pH changes during the delivery process. The particle maintains negative charge at neutral pH for reduced cytotoxicity and efficient cellular uptake, then transitions to positive charge in acidic endosomes to facilitate nucleic acid encapsulation. This dynamic charge transition resolves the contradiction between encapsulation efficiency and membrane penetration.
3Object-affected harmful factors
If a non-positive charged lipid particle is used, then cytotoxicity is reduced, but electrostatic interaction with nucleic acid deteriorates
Solution Approach 1:
The phospholipid's charge state is dynamically changed by pH adjustment. In the acidic environment of endosomes/lysosomes (pH 4.5-6.5), the phospholipid becomes positively charged to enable strong electrostatic interaction with negatively charged nucleic acids for efficient encapsulation. In neutral pH environments (cytoplasm, extracellular space), the phospholipid remains negatively charged to minimize cytotoxicity. This environment-dependent charge transition resolves the contradiction between cytotoxicity reduction and electrostatic interaction.
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 phospholipid particles efficiently deliver medicinal substances like mRNA with reduced cytotoxicity, enhancing their effect and stability in the body.
Implementation Method 1
administering a negatively charged nucleic acid typically involves the use of a positively charged lipid to cause electrostatic interaction
Data Source
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AI summary
The present invention provides a lipid particle that is not positively charged at a pH of the body fluid (typically in the neutral range), and that enables more efficient onset of the effect of a medicinal substance encapsulated in the lipid particle; and a lipid for forming the lipid particle. The present invention provides a phospholipid represented by formula (1): wherein R1 and R2 are the same or different, and each represents a chain hydrocarbon group; R3, R4, and R5 are the same or different, and each represents a C1-CS hydrocarbon group; m represents 1 or 2; n represents 1 or 2; and p represents a natural number of 1 to 3.