Chimeric Antigen Nucleic Acid Delivery via Receptor-Mediated Endocytosis
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Solution Overview
Problem
Current methods for delivering nucleic acids, such as siRNAs, face challenges in targeted delivery to specific cells, dosage minimization, and toxicity reduction, hindering their effectiveness in therapeutic applications, particularly in cancer and viral infections.
Innovation Solution
Development of chimeric antigens comprising a nucleic acid binding domain corresponding to the HBV core protein and a target binding domain for receptor-specific binding, allowing for targeted delivery and internalization of nucleic acids into target cells, enhancing gene silencing and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody-mediated delivery or liposomal delivery is used to target nucleic acids to specific cells, then preferential accumulation in target cells is achieved, but delivery efficiency and cellular uptake remain insufficient
Solution Approach 1:
The patent merges the targeting capability of antibody fragments with the cellular uptake promotion of protamine into a single chimeric protein. The antibody fragment portion provides specific binding to cell surface receptors for targeted delivery, while the protamine portion promotes cellular internalization through receptor-mediated endocytosis, thereby simultaneously improving both targeted delivery efficiency and cellular uptake rate.
Solution Approach 2:
The chimeric protein is a composite molecule combining two distinct functional domains: an antibody fragment domain for specific targeting and a protamine domain for enhanced uptake. This composite structure allows the single molecule to perform multiple functions that were previously achieved by separate delivery systems, resolving the contradiction between targeted delivery and cellular uptake efficiency.
2Reliability
If higher dosages of nucleic acid therapeutics are administered to improve therapeutic effect, then gene silencing efficacy increases, but toxicity and cost increase
Solution Approach 1:
The chimeric protein enables the nucleic acid therapeutic to self-target and self-deliver to the appropriate cells through receptor-mediated endocytosis. This self-service delivery mechanism ensures that the nucleic acid reaches its target efficiently at lower dosages, reducing the need for high-dose administration and thereby lowering toxicity while maintaining gene silencing efficacy.
Solution Approach 2:
The chimeric protein acts as an intermediary carrier that facilitates efficient cellular uptake of nucleic acids through protamine-mediated endocytosis. This intermediary mechanism improves delivery efficiency, allowing lower dosages of nucleic acid therapeutics to achieve the desired therapeutic effect, thus reducing toxicity associated with high-dose administration.
3Adaptability or versatility
If non-specific nucleic acid delivery is used, then distribution is widespread, but toxicity to normal tissues increases
Solution Approach 1:
The chimeric protein imparts local quality to the nucleic acid delivery by providing specific targeting capability through the antibody fragment domain. This domain binds to cell surface receptors that are selectively expressed on target cells, ensuring that the nucleic acid therapeutic is delivered specifically to the intended tissue or cell type while minimizing distribution to and toxicity in normal tissues.
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 chimeric antigen system enables efficient delivery and silencing of target genes within specific cells, boosting immune responses and reducing toxicity, thereby improving therapeutic efficacy in cancer and viral infections.
Implementation Method 1
a nucleic acid binding domain comprising an amino acid sequence corresponding to HBV core protein or a fragment thereof
Implementation Method 2
a target binding domain comprising a ligand for binding to a receptor on a target cell
Implementation Method 3
it has been suggested that such ligands can further be conjugated to delivery agents, such as liposomes, to promote uptake into target cells by receptor mediated endocytosis
Data Source
AI summary
Methods and compositions are provided for delivery of therapeutic nucleic acids to a target cell. A chimeric antigen is provided to encapsulate, bind, or otherwise carry a nucleic acid molecule to a target cell where the chimeric antigen and nucleic acid are internalized by receptor-mediated endocytosis. The chimeric antigen has a nucleic acid interaction domain, a target binding domain, and an immune response domain that may include a target antigen. Targeting is generally provided by the specificity of the target binding domain for a particular target cell receptor, but may also be provided by inclusion of a targeting antigen within the immune response domain. The combined delivery of chimeric antigen and nucleic acid, which may be a siRNA, may be synergistic in certain applications, for example in breaking host tolerance to a virus or in providing immunostimulation.