Nanoparticle Peptide Delivery via Enzymatic Linker Cleavage
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Solution Overview
Problem
Current methods for intracellular peptide delivery, such as immunotherapy, face challenges in effectively delivering peptides to intracellular compartments to stimulate a CTL response or target intracellular drug sites, with free peptides often displaying poor uptake by cells.
Innovation Solution
Nanoparticles with a core comprising metal or semiconductor atoms and a corona of ligands, including a peptide covalently attached via specific linkers, facilitate cellular uptake and release of peptides for interaction with intracellular targets, enabling efficient delivery and processing by antigen-presenting cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If free peptides are administered for intracellular delivery, then the peptides can potentially reach intracellular targets, but the uptake by cells is poor
Solution Approach 1:
The patent uses nanoparticales as intermediary carriers to deliver peptides into cells. The nanoparticle comprises a core and a corona where peptides are covalently attached via specific linkers (such as GFLG, FLAAY, or AAY sequences). The nanoparticle mediates cellular uptake through endocytosis, and intracellular release is achieved through proteasomal or lysosomal cleavage of the linker, thereby solving the poor uptake problem of free peptides while maintaining delivery effectiveness
Solution Approach 2:
The patent changes the physical and chemical parameters of peptide delivery by conjugating peptides to nanoparticle surfaces through controllable linker molecules. The linker design (with specific amino acid sequences like GFLG recognized by calreticulin or FLAAY/AAY recognized by cathepsin B) allows controlled intracellular release through enzymatic cleavage, transforming the delivery system from passive free peptide administration to an active, targeted, and controllable release mechanism that significantly improves both uptake efficiency and delivery effectiveness
2Reliability
If viral vectors are used to deliver peptides, then intracellular peptide production can be achieved, but the complexity of the delivery system increases
Solution Approach 1:
The patent extracts the essential function of viral vectors (intracellular delivery) while removing their complexity. Instead of using viral vectors that require transfection and rely on cellular translational machinery, the invention directly delivers pre-synthesized peptides attached to nanoparticle carriers. The nanoparticle system achieves intracellular delivery through endocytosis without requiring viral components, plasmid DNA, or complex transfection protocols, thereby maintaining reliable intracellular peptide delivery while dramatically simplifying the overall system
Solution Approach 2:
The patent segments the delivery system into distinct functional components: a nanoparticle core, a corona with covalently attached peptides via controllable linkers, and specific recognition elements. This segmentation allows each component to be optimized independently and simplifies the overall system compared to viral vectors, which integrate multiple complex functions (genetic material delivery, transcription, translation, and regulation) into a single complicated biological system
Data Source
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AI summary
The present invention provides nanoparticles and compositions comprising such nanoparticles, as well as methods for intracellular delivery of peptides, and methods of producing nanoparticles and related products. The nanoparticles comprise a core comprising a metal and/or a semiconductor atom; and a corona comprising a plurality of ligands covalently linked to the core, wherein at least a first ligand of said plurality comprises a carbohydrate moiety that is covalently linked to the core via a first linker, and wherein at least a second ligand of said plurality comprises a peptide of choice that is covalently linked to the core via a second linker. The second linker comprises a peptide portion and a non- peptide portion, wherein said peptide portion of said second linker comprises the sequence X1X2Z1, wherein: X1 is an amino acid selected from A and G; X2 is an amino acid selected from A and G; and Z1 is an amino acid selected from Y and F.