Self-Assembling Polypeptide Nanoparticles for Oligonucleotide Delivery
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Solution Overview
Problem
Existing oligonucleotide delivery systems face challenges such as suboptimal pharmacokinetic properties, susceptibility to nucleases, urinary excretion, and immune responses, with virus-like particles being complex and costly to produce and associated with safety concerns.
Innovation Solution
Design and production of non-naturally occurring polypeptides that self-assemble into nanoparticles capable of encapsulating and delivering negatively charged macromolecules like oligonucleotides, which are efficiently taken up by mammalian cells and conditionally release their cargo to modulate gene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If virus-like particles are used as delivery systems, then oligonucleotide delivery capability is improved, but manufacturing complexity and cost increase significantly
Solution Approach 1:
The patent uses computationally designed protein sequences that copy the self-assembly capabilities of viral capsids but with simplified, non-viral sequences. These designed proteins replicate the essential function of virus-like particles (encapsulating and delivering oligonucleotides) without requiring complex viral production systems, thereby reducing manufacturing complexity while maintaining delivery capability
Solution Approach 2:
The patent employs recombinant protein expression systems that produce disposable, non-infectious protein nanocages. These particles are designed to be produced economically through standard molecular biology techniques and used as single-use delivery vehicles, eliminating the need for complex, expensive viral manufacturing infrastructure while achieving comparable delivery results
2Reliability
If virus-like particles are used as delivery systems, then oligonucleotide delivery capability is improved, but safety concerns arise
Solution Approach 1:
The patent extracts only the essential functional elements needed for oligonucleotide delivery (self-assembly into nanocages, cargo encapsulation, cellular uptake) while removing all harmful viral components (infectivity, immunogenicity, biosafety risks). The resulting protein nanocages are composed of de novo designed sequences that have no viral origin, thereby eliminating safety concerns while preserving delivery capability
Solution Approach 2:
The patent converts the potential harm of viral delivery systems (immunogenicity, safety risks) into a benefit by designing proteins that explicitly avoid these problems. The computationally optimized sequences are engineered to be non-immunogenic and non-infectious, turning the limitation of non-viral systems into an advantage by providing a safer alternative that still achieves effective delivery
3Ease of manufacture
If simple delivery materials are used, then safety and ease of manufacture are improved, but delivery efficiency decreases
Solution Approach 1:
The patent systematically optimizes key parameters of the protein sequences (charge distribution, hydrophobicity patterns, structural motifs) to maximize delivery efficiency. Through computational design, the sequences are tuned to achieve optimal self-assembly behavior, cargo binding affinity, and cellular uptake characteristics, thereby achieving high delivery efficiency with simple, recombinantly produced proteins
Solution Approach 2:
The patent creates composite functional elements by combining multiple design features within the protein sequences: self-assembly domains, cargo-binding regions, and cell-penetration motifs are integrated into single polypeptide chains. This composite approach allows simple recombinant proteins to exhibit multiple functions simultaneously, achieving high delivery efficiency without complex manufacturing requirements
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 provide a safe, efficient, and scalable platform for intracellular delivery of therapeutic oligonucleotides, minimizing undesirable properties of prior art delivery vehicles and allowing controlled cargo release.
Implementation Method 1
designed and non-naturally occurring novel polypeptides that are not only capable of self-assembling into nanoparticles
Implementation Method 2
nanoparticles are furthermore capable of encapsulating negatively charged macromolecules such as oligonucleotides with high binding affinity
Data Source
AI summary
The present invention relates to polypeptides self-assembling into nanoparticles. In particular, the invention relates to a polypeptide comprising an amino acid sequence I (SEQ ID NO: 1), a nucleic acid sequence encoding said polypeptide, a nanoparticle comprising at least one polypeptide of the invention, a complex comprising said nanoparticle and one or more cargo molecules, and a method for transfecting a cell with said complex.