RNA-nanostructured double robots and methods of use thereof
Inventors
Chang, Yung • Yan, Hao • QI, Xiaodong • ZHANG, Fei
Assignees
Publication Number
US-12312589-B2
Publication Date
2025-05-27
Expiration Date
2039-01-10
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Abstract
Described herein are immuno-stimulatory RNA nanostructures (which comprises a single-stranded RNA (ssRNA) molecule, wherein the ssRNA molecule forms at least one paranemic cohesion crossover), as well as compositions and methods of use thereof.
Core Innovation
The invention provides immuno-stimulatory RNA nanostructures, referred to as RNA nanostructure robots or RNA origami, comprising self-assembled single-stranded RNA molecules that form defined three-dimensional shapes, such as rectangular scaffolds, via paranemic cohesion crossovers. These nanostructures can be engineered to include a variety of functional modules, such as aptamers, cargo molecules, capture strands, and targeting moieties, and can incorporate additional components, including peptides or therapeutic agents. The double-robot configuration consists of two independent RNA nanostructures (NR1 and NR2), linked by a tunable linker, which can be designed to respond to specific physiological triggers, such as pH changes or the presence of certain cytokines.
The invention addresses the problem that conventional synthetic RNA-based adjuvants, such as polyIC, are susceptible to nuclease degradation in vivo, leading to limited stability and delivery efficacy. Additionally, prior ligands often suffered from high toxicity, heterogeneity, and lack of control over immune activation, which restricted their utility as safe and effective molecular cargo delivery platforms and immunotherapy adjuvants, especially in cancer contexts.
The core innovation is the design of a versatile, stable, and programmable RNA nanostructure robot capable of serving both as a molecular scaffold for agent delivery and as an immuno-stimulatory adjuvant. The RNA nanostructure can be further functionalized with fastener strands, targeting strands (including aptamers specific for tumor markers like nucleolin), and cargo such as tumor-specific antigens or checkpoint inhibitors. The nanostructure may undergo structural transformations in response to environmental cues, enabling controlled release of encapsulated agents within the tumor microenvironment. Methods for producing, assembling, and applying these RNA nanostructure robots in therapeutic compositions and vaccine formulations are also disclosed.
Claims Coverage
The independent claims provide two major inventive features covering the RNA nanostructure robot composition and its use in treating cancer and activating the immune system via TLR3 in a human subject.
RNA nanostructure robot composition for cancer treatment
A composition comprising an RNA nanostructure robot with the sequence (R3)n—NR1-L-NR2—(R4)m, where NR1 and NR2 independently are RNA nanostructures each comprising a nucleic acid sequence having at least about 90% sequence identity to specific sequences (SEQ ID NO:1 or SEQ ID NO:9) that self-assemble into respective first and second scaffolds; L is a linker operably linking NR1 to NR2; R3 and R4 are independently chosen from fastener strands, aptamers, cargo molecules, capture strands, targeting strands, and H; n is 1 to 20 and m is 0 to 20; the composition further includes a pharmaceutically acceptable carrier; and the method comprises administering a therapeutically effective amount to a human subject for cancer treatment.
RNA nanostructure robot composition for immune system activation via TLR3 signaling
A composition comprising an RNA nanostructure robot structured as (R3)n—NR1-L-NR2—(R4)m (with the same definitions for NR1, NR2, R3, R4, L, n, and m as above), and a pharmaceutically acceptable carrier, for use in a method of activating or stimulating the immune system by triggering the toll-like receptor 3 (TLR3) signaling pathway in a human subject by administering a therapeutically effective amount of the composition.
The claims broadly cover compositions of defined RNA nanostructure robots with tunable modular elements for use in cancer therapy and immune system stimulation, specifying sequence identity, modular composition, and therapeutic utility.
Stated Advantages
The RNA nanostructure robots are highly stable and exhibit increased resistance to nuclease digestion, enabling longer circulation and higher potency in vivo.
The nanostructure robots are scalable for production, possessing well-defined structure and uniformity, ensuring reproducibility and lower production costs.
The robots have superior internalization by immune cells, obviating the need for additional packaging to promote phagocytosis.
They selectively activate immune signaling pathways, particularly TLR3, which is required for adaptive anti-cancer or anti-viral immunity, while reducing activation of pathways associated with systemic toxicity.
The platform enables safe, programmable, targeted delivery and release of therapeutic agents or checkpoint inhibitors in response to specific stimuli, enhancing both anti-tumor immunity and counteracting immunosuppression.
RNA nanostructure robots offer improved safety profiles, exhibiting low toxicity due to selective pathway activation and reduced risk of cytokine storm compared to conventional adjuvants.
The RNA nanostructure robots possess a programmable and versatile scaffold that can incorporate a variety of functional modules, aptamers, and therapeutic agents for tailored immunotherapy.
Documented Applications
Treatment of various cancers in human subjects, including breast cancer, ovarian cancer, melanoma, lung cancer, colon cancer, lymphoma, sarcoma, and other solid and hematological tumors.
Activation or stimulation of the immune system by specifically triggering the TLR3 signaling pathway.
Inhibition of tumor growth in subjects through administration of the RNA nanostructure robot compositions.
Use as an adjuvant for vaccine formulations, including construction of tumor-specific vaccines and induction of anti-tumor immune responses.
Manufacture of a medicament for inducing a tumor necrosis response in a subject.
Prophylactic or therapeutic treatment of diseases or disorders requiring enhanced immune response, including infectious diseases and hyperproliferative conditions.
Targeted delivery and controlled release of therapeutic agents, such as checkpoint inhibitors, within the tumor microenvironment.
Diagnostic and therapeutic use in compositions or kits for inducing immune responses or treating diseases in mammalian subjects.
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