Granted Patent
B2
US 12,298,300 · App. 17/232,631 · Granted May 13, 2025
Single-molecule electronic sequence detector and methods of use
Inventors:
Stuart Lindsay (Scottsdale, AZ); Karen Anderson (Scottsdale, AZ); Mark Knappenberger (Scottsdale, AZ); Sepideh Afsari Mamaghani (Scottsdale, AZ); Jacob L. Swett (Tempe, AZ)
Assignees:
Arizona Board of Regents on behalf of Arizona State University; Recognition Analytix, Inc.
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Abstract
The present disclosure provides devices, systems, and methods related to single molecule detection. In particular, the present disclosure provides devices and methods for sequence-specific detection of a nucleic acid target using current fluctuations as a readout for protein binding to the nucleic acid target. As described herein, certain aspects of the bioelectronic devices and method can be used to detect and identify any nucleic acid target for the purpose of diagnosis and/or treatment.
Claims (33)
1. A bioelectronic device for detecting a target nucleic acid comprising:
a first electrode;
a second electrode; and
at least one CRISPR-associated protein comprising a modification to form a chemical bond with the first and the second electrodes, wherein the modification comprises attaching at least two linkers to the CRISPR-associated protein, and wherein at least one of the at least two linkers is attached to each of the first and second electrodes.
2. The device of claim 1 , wherein the modification allows an electrical current to pass through the CRISPR-associated protein, and wherein binding of the CRISPR-associated protein to a target nucleic acid causes a shift in the current.
3. The device of claim 1 , wherein the CRISPR-associated protein is a Cas family member protein selected from the group consisting of Cas1, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas10, Cas12, Cas13, Cas14, their nuclease-deficient dCas equivalents, and any variants or derivatives thereof.
4. The device of claim 1 , wherein the CRISPR-associate protein is Cas9 protein or dCas9.
5. The device of claim 1 , wherein the linker is attached to an inactive region of the CRISPR-associated protein via a covalent chemical bond.
6. The device of claim 1 , wherein the modification comprises biotinylating the CRISPR-associate protein.
7. The device of claim 1 , wherein the linker comprises thio-streptavidin.
8. The device of claim 1 , wherein the CRISPR-associate protein and the first and second electrodes are biotinylated, and wherein the linker comprises a streptavidin molecule comprising at least two biotin binding sites.
9. The device of claim 1 , wherein the modification comprises a HaloTag fusion protein and a chloroalkane linker.
10. The device of claim 1 , wherein the first and/or the second electrode comprises gold, palladium, platinum, silver, copper, or any alloys thereof.
11. The device of claim 1 , wherein the first electrode comprises a dielectric layer at least partially covering a top surface of the first electrode.
12. The device of claim 11 , wherein the thickness of the dielectric layer is from about 1 nm to about 50 nm.
13. The device of claim 1 , wherein the first electrode and second electrode are positioned so that between about a 1 nm and about a 50 nm gap is formed between the two electrodes.
14. The device of claim 13 , wherein the gap is from about 2 to about 8 nm.
15. A method of detecting a target nucleic acid using the bioelectronic device of claim 1 , the method comprising:
combining the bioelectronic device and the target nucleic acid with a guide RNA;
applying a voltage bias between the first and the second electrode that is 100 mV or less; and
detecting a shift in current upon binding of the CRISPR-associated protein and the guide RNA to the target nucleic acid.
16. The method of claim 15 , wherein the guide RNA is complementary to a portion of the target nucleic acid.
17. The method of claim 15 , wherein the shift in current comprises a decrease in current as compared to the current when the CRISPR-associated protein is not bound to the target nucleic acid.
18. The method of claim 15 , wherein the target nucleic acid is contained in or derived from a sample from a subject.
19. The method of claim 18 , wherein the detection of the shift in current indicates that the target nucleic acid is present in the sample.
20. The method of claim 18 , wherein the sample is selected from the group consisting of a blood sample, a serum sample, a plasma sample, a saliva sample, a urine sample, a stool sample, and a mucosal sample.
21. The method of claim 15 , wherein the target nucleic acid is DNA or RNA.
22. The method of claim 15 , wherein the target nucleic acid is derived from or associated with a pathogenic organism.
23. The method of claim 15 , wherein the target nucleic acid is derived from or associated with a disease or condition.
24. The method of claim 15 , wherein the target nucleic acid is derived from or associated with an engineered organism.
25. The method of claim 22 , wherein the target nucleic acid is derived from or associated with a SARS-CoV-2 infection.
26. A system comprising a plurality of the bioelectronic devices of claim 1 .
27. The system of claim 26 , wherein the plurality of bioelectronic devices are configured to detect more than one target nucleic acid based on corresponding guide RNA sequences.
Assignments (6)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 3, 2025
From: SWETT, JACOB L.
To: RECOGNITION ANALYTIX INC.
Reel/Frame 070730/0206 →
CORRECTIVE ASSIGNMENT TO CORRECT THE CORRECT THE ASSIGNOR BY DELATING CONVEYING PARTY ASSIGNOR JACOB L. SWETT PREVIOUSLY RECORDED AT REEL: 56928 FRAME: 817. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT.
Recorded Mar 31, 2025
From: LINDSAY, STUART; ANDERSON, KAREN; KNAPPENBERGER, MARK; AFSARI MAMAGHANI, SEPIDEH
To: ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY
Reel/Frame 070690/0102 →
CORRECTIVE ASSIGNMENT TO CORRECT THE CORRECT THE ASSIGNOR BY DELATING CONVEYING PARTY ASSIGNOR JACOB L. SWWETT PREVIOUSLY RECORDED AT REEL: 59014 FRAME: 744. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT.
Recorded Mar 31, 2025
From: LINDSAY, STUART; ANDERSON, KAREN; KNAPPENBERGER, MARK; AFSARI MAMAGHANI, SEPIDEH
To: ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY
Reel/Frame 070690/0108 →
CONFIRMATORY LICENSE
Recorded Nov 10, 2023
From: ARIZONA STATE UNIVERSITY, TEMPE CAMPUS
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065548/0083 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 15, 2022
From: LINDSAY, STUART; ANDERSON, KAREN; KNAPPENBERGER, MARK; MAMAGHANI, SEPIDEH AFSARI; SWETT, JACOB L.
To: ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY
Reel/Frame 059014/0744 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 21, 2021
From: LINDSAY, STUART; ANDERSON, KAREN; KNAPPENBERGER, MARK; AFSARI MAMAGHANI, SEPIDEH; SWETT, JACOB L.
To: ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY
Reel/Frame 056928/0817 →
Continuity (2)
Provisional Application
63011799
· Apr 17, 2020
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