Polyvalent-Molecule Lipid Nanoparticles for Nucleic Acid Delivery
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Solution Overview
Problem
Current nucleic acid therapeutics face challenges in delivering therapeutic nucleic acids to the myeloid compartment due to rapid clearance, degradation, and immunostimulatory adverse effects, with existing delivery systems lacking the ability to target this compartment effectively and often causing unwanted immune responses.
Innovation Solution
Nanoparticles stabilized by apolipoprotein or its derivatives, incorporating polyvalent molecules that bind strongly to nucleic acids and shield them from degradation, while targeting the myeloid cell compartment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acids are administered systemically, then they can reach target cells, but they are rapidly cleared from circulation due to kidney filtration and nuclease degradation
Solution Approach 1:
The patent uses apolipoprotein A-1 as an intermediary carrier to deliver nucleic acids. The apolipoprotein binds to the nucleic acid and forms a complex that mimics natural lipoprotein particles, enabling the nucleic acid to circulate in the bloodstream without being rapidly cleared by kidney filtration or nucleases. This intermediary carrier protects the nucleic acid while maintaining its delivery capability to target cells.
Solution Approach 2:
The patent modifies the physical and chemical parameters of the nucleic acid delivery system by conjugating it to apolipoprotein A-1. This changes the size, charge, and surface properties of the nucleic acid, transforming it from a small anionic molecule that is rapidly filtered by kidneys into a larger complex that circulates longer in the bloodstream while still able to reach target cells.
2Reliability
If nucleic acids are delivered to target cells, then therapeutic effects can be achieved, but they cannot readily pass cellular membranes
Solution Approach 1:
The apolipoprotein A-1 acts as a mediator that facilitates cellular uptake of the nucleic acid. By forming a complex with the nucleic acid, the apolipoprotein enables the cargo to interact with cellular membranes and be internalized by target cells, overcoming the natural barrier of cellular membranes that normally prevent nucleic acid entry.
3Reliability
If exogenous nucleic acids are administered, then therapeutic effects can be achieved, but they provoke an immune response leading to rapid clearance and adverse effects
Solution Approach 1:
The apolipoprotein A-1 serves as a protective intermediary that shields the exogenous nucleic acid from immune system recognition. By binding to the nucleic acid, the apolipoprotein prevents immune cells and proteins from detecting and attacking the foreign nucleic acid, thereby reducing immunostimulatory effects and preventing rapid clearance by the immune system.
Solution Approach 2:
The patent converts the potential harm of immune recognition into a benefit by using the apolipoprotein-nucleic acid complex structure. The complex mimics natural lipoprotein particles that are normally present in the bloodstream, thereby 'disguising' the exogenous nucleic acid as a natural component and preventing immune activation while still allowing therapeutic delivery.
4Reliability
If conventional lipid nanoparticles are used for delivery, then nucleic acids can be protected, but they contain PEG-conjugated lipids associated with hypersensitivity reactions and anaphylaxis
Solution Approach 1:
The patent extracts and removes the problematic PEG-conjugated lipids from the nanoparticle formulation while retaining the protective and delivery functions. By using apolipoprotein A-1 instead of PEG-lipids, the invention eliminates the harmful PEG components that cause hypersensitivity reactions and anaphylaxis, while still providing nucleic acid protection and cellular delivery capabilities.
Solution Approach 2:
The patent uses a composite material approach by combining apolipoprotein A-1 with nucleic acid to form a novel delivery complex. This composite structure provides the protective and delivery functions previously achieved by PEG-lipid nanoparticles, but without the associated immunogenicity and hypersensitivity problems.
5Reliability
If conventional LNPs are used for systemic administration, then hepatocytes can be targeted, but accumulation in the liver is predominant rather than in the myeloid compartment
Solution Approach 1:
The patent changes the surface properties and recognition parameters of the delivery particle by using apolipoprotein A-1 instead of conventional LNP components. This parameter change alters the tissue distribution pattern from predominant liver accumulation to targeted delivery to the myeloid compartment, while maintaining efficient targeting capabilities.
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 nanoparticles efficiently deliver nucleic acids to lymphoid organs like the bone marrow and spleen, reducing immunostimulatory effects and enhancing therapeutic efficacy by protecting the nucleic acids from degradation and rapid clearance.
Implementation Method 1
The polyvalent molecule has multiple positively ionizable and/or cationic groups that can efficiently bind and capture (or complex) nucleic acids
Implementation Method 2
nanoparticles comprising a nucleic acid, a polyvalent molecule and a stabilizer, preferably an apolipoprotein, an apolipoprotein derivative, an apolipoprotein mimetic and/or an apolipoprotein mimetic derivative
Implementation Method 3
The apolipoprotein stabilizer also acts as a targeting moiety as it is capable of directing the nanoparticle to the myeloid cell compartment
Data Source
AI summary
The invention relates to nanoparticles particularly for nanoparticles suitable for the delivery of a nucleic acid to a cell. The nanoparticles comprise polyvalent molecules to stabilise the nucleic acid molecules in the nanoparticles. Particularly the polyvalent molecules have a dendrimer like structure. The invention further relates to manufacturing nanoparticles, and uses of such nanoparticles in the treatment of a disease.