Plant viral RNA delivery nanoparticles and uses thereof
Inventors
Assignees
Case Western Reserve University
Publication Number
US-12203073-B2
Publication Date
2025-01-21
Expiration Date
2040-12-21
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Abstract
A nanoparticle includes an icosahedral-shaped plant virus particle; an RNAi construct; and one or more endolysosomal release agents, wherein the RNAi construct is noncovalently loaded within the icosahedral-shaped plant virus particle.
Core Innovation
The invention provides nanoparticles based on icosahedral-shaped plant virus particles, particularly cowpea chlorotic mottle virus (CCMV), that are noncovalently loaded with RNA interference (RNAi) constructs such as small interfering RNAs (siRNAs) and further equipped with one or more endolysosomal release agents. The RNAi constructs can be targeted to specific oncogenes, such as the forkhead box transcription factor (FOXA1), and are encapsulated within the CCMV particle. The nanoparticle may additionally feature an L17E M-lycotoxin peptide as an endolysosomal release agent covalently linked to the CCMV exterior.
The described technology addresses the challenge of delivering siRNA therapeutics to mammalian cells for gene silencing, especially in the context of cancer. Traditional 'naked' siRNAs face issues of instability in plasma, lack of targeting, and inefficient cell uptake due to their negative charge. Current delivery platforms, including mammalian viral vectors and non-viral systems, suffer from safety, immunogenicity, or instability concerns. Thus, there is a continued need for an effective gene delivery vehicle for siRNA applications.
By utilizing icosahedral-shaped plant virus nanoparticles like CCMV, which cannot infect or replicate in mammalian cells, the invention presents a strategy for safe and efficient siRNA delivery. The plant virus particle structure enables precise encapsulation of RNAi cargo, while conjugation with an endolysosomal release agent, such as the cell-penetrating L17E peptide, enhances cellular uptake and endolysosomal escape, promoting efficient gene silencing in targeted cancer cells. The nanoparticles can be administered systemically or locally, and are suited for use alongside other anticancer agents or therapies.
Claims Coverage
The independent claims cover two main inventive features involving CCMV nanoparticles loaded with siRNA and possessing an L17E M-lycotoxin peptide, as well as their use in treating hormone dependent breast cancer.
CCMV nanoparticle loaded with siRNA and L17E M-lycotoxin peptide
A nanoparticle comprising: - Cowpea chlorotic mottle virus (CCMV) - siRNA noncovalently loaded within the CCMV - An L17E M-lycotoxin peptide The L17E M-lycotoxin peptide can be linked to the exterior surface of the CCMV. The siRNA may target oncogenes, such as forkhead box transcription factor (FOXA1).
Method of treating hormone dependent breast cancer using a CCMV-siRNA-L17E nanoparticle
A method comprising: - Administering to a subject a therapeutically effective amount of a nanoparticle including: - Cowpea chlorotic mottle virus (CCMV), - siRNA targeting the forkhead box transcription factor (FOXA1) oncogene, and - An L17E M-lycotoxin peptide endolysosomal release agent, - Wherein the siRNA is encapsulated within the CCMV. This method may include: - Systemic administration of the nanoparticle - Use in combination with an additional anticancer agent or therapy, including antitumor or anti-hormonal agents, or therapies such as radiation therapy, brachytherapy, or ablation.
The inventive features focus on the composition of a CCMV nanoparticle encapsulating siRNA with a cell-penetrating L17E peptide, and its medical use for treating hormone dependent breast cancer, optionally in conjunction with other anticancer agents and therapies.
Stated Advantages
Plant virus-based nanoparticles provide a safer alternative for delivering siRNA therapeutics because they are unable to infect or replicate in mammalian cells.
The technology enables structure-based design of high-precision, scalable, and temperature-stable nanodrug delivery systems suitable for high-yield manufacturing.
Encapsulation of siRNA within icosahedral-shaped plant virus particles like CCMV increases stability and enables efficient gene silencing via RNAi.
Conjugation with endolysosomal release agents such as the L17E M-lycotoxin peptide enhances cancer cell uptake and facilitates endolysosomal escape of the cargo.
The nanoparticles can avoid the need for additional transfection agents, such as Lipofectamine, by enabling efficient cytoplasmic delivery of siRNA.
In planta production of the plant virus particles prevents endotoxin contamination, further increasing safety and quality.
Documented Applications
Use of CCMV siRNA-loaded nanoparticles with L17E M-lycotoxin peptide for treating hormone dependent breast cancer in a subject.
Method of delivering oncogene-targeted siRNAs, particularly those targeting FOXA1, to cancer cells to achieve gene silencing and potential inhibition of cancer cell proliferation.
Systemic or local administration of the nanoparticles for cancer therapy, optionally in combination with additional anticancer agents, anti-hormonal agents, or therapies such as radiation therapy, brachytherapy, or ablation therapy.
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