Nanoparticles having oligonucleotides attached thereto and uses therefor

A method of detecting nucleic acid having at least two portions comprising:

• providing a substrate having a first type of nanoparticles attached thereto, the nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of a nucleic acid to be detected;
• contacting said nucleic acid with the nanoparticles attached to the substrate under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with said nucleic acid;
• providing a second type of nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to one or more other portions of the sequence of said nucleic acid;
• contacting said nucleic acid bound to the substrate with the second type of nanoparticles under conditions effective to allow hybridization of the oligonucleotides on the second type of nanoparticles with said nucleic acid;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• providing a substrate having a first type of nanoparticles attached thereto, the nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of a nucleic acid to be detected;
• contacting said nucleic acid with the nanoparticles attached to the substrate under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with said nucleic acid;
• providing a second type of nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to one or more other portions of the sequence of said nucleic acid;
• contacting said nucleic acid bound to the substrate with the second type of nanoparticles under conditions effective to allow hybridization of the oligonucleotides on the second type of nanoparticles with said nucleic acid;
• providing a binding oligonucleotide having a selected sequence having at least two portions, the first portion being complementary to at least a portion of the sequence of the oligonucleotides on the second type of nanoparticles;
• contacting the binding oligonucleotide with the second type of nanoparticles bound to the substrate under conditions effective to allow hybridization of the binding oligonucleotide to the oligonucleotides on the nanoparticles;
• providing a third type of nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to the sequence of a second portion of the binding oligonucleotide;
• contacting the third type of nanoparticles with the binding oligonucleotide bound to the substrate under conditions effective to allow hybridization of the binding oligonucleotide to the oligonucleotides on the nanoparticles;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• contacting a nucleic acid to be detected with a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the substrate with said nucleic acid;
• contacting said nucleic acid bound to the substrate with a first type of nanoparticles having one or more types of oligonucleotides attached thereto, at least one of the types of oligonucleotides having a sequence complementary to a second portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with said nucleic acid;
• contacting the first type of nanoparticles bound to the substrate with a second type of nanoparticles having oligonucleotides attached thereto, the oligonucleotides on the second type of nanoparticles having a sequence complementary to at least a portion of the sequence of one of the types of oligonucleotides on the first type of nanoparticles, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the first and second types of nanoparticles;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• contacting a nucleic acid to be detected with a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the substrate with said nucleic acid;
• contacting said nucleic acid bound to the substrate with a type of nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a second portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with said nucleic acid;
• contacting the substrate with silver stain to produce a detectable change;
• and
• observing the detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• contacting a nucleic acid to be detected with a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the substrate with said nucleic acid;
• contacting said nucleic acid bound to the substrate with liposomes having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the liposomes with said nucleic acid;
• contacting the liposomes bound to the substrate with a first type of nanoparticles having at least a first type oligonucleotides attached thereto, the first type of oligonucleotides having a hydrophobic group attached to the end not attached to the nanoparticles, the contacting taking place under conditions effective to allow attachment of the oligonucleotides on the nanoparticles to the liposomes as a result of hydrophobic interactions;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising

• contacting a nucleic acid to be detected with a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the substrate with said nucleic acid;
• contacting said nucleic acid bound to the substrate with liposomes having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the liposomes with said nucleic acid;
• contacting the liposomes bound to the substrate with a first type of nanoparticles having at least a first type oligonucleotides attached thereto, the first type of oligonucleotides having a hydrophobic group attached to the end not attached to the nanoparticles, the contacting taking place under conditions effective to allow attachment of the oligonucleotides on the nanoparticles to the liposomes as a result of hydrophobic interactions;
• contacting the first type of nanoparticles bound to the liposomes with a second type of nanoparticles having oligonucleotides attached thereto,
• the first type of nanoparticles having a second type of oligonucleotides attached thereto which have a sequence complementary to at least a portion of the sequence of the oligonucleotides on the second type of nanoparticles,
• the oligonucleotides on the second type of nanoparticles having a sequence complementary to at least a portion of the sequence of the second type of oligonucleotides on the first type of nanoparticles,
• the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the first and second types of nanoparticles;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• providing a substrate having a first type of nanoparticles attached thereto, the nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of a nucleic acid to be detected;
• contacting said nucleic acid with the nanoparticles attached to the substrate under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with said nucleic acid;
• providing an aggregate probe comprising at least two types of nanoparticles having oligonucleotides attached thereto, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of some of the oligonucleotides attached to them, at least one of the types of nanoparticles of the aggregate probe having oligonucleotides attached thereto which have a sequence complementary to a second portion of the sequence of said nucleic acid;
• contacting said nucleic acid bound to the substrate with the aggregate probe under conditions effective to allow hybridization of the oligonucleotides on the aggregate probe with said nucleic acid;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• providing a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of a nucleic acid to be detected;
• providing an aggregate probe comprising at least two types of nanoparticles having oligonucleotides attached thereto, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of some of the oligonucleotides attached to them, at least one of the types of nanoparticles of the aggregate probe having oligonucleotides attached thereto which have a sequence complementary to a second portion of the sequence of said nucleic acid;
• contacting said nucleic acid, the substrate and the aggregate probe under conditions effective to allow hybridization of said nucleic acid with the oligonucleotides on the aggregate probe and with the oligonucleotides on the substrate;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• providing a substrate having oligonucleotides attached thereto;
• providing an aggregate probe comprising at least two types of nanoparticles having oligonucleotides attached thereto, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of some of the oligonucleotides attached to them, at least one of the types of nanoparticles of the aggregate probe having oligonucleotides attached thereto which have a sequence complementary to a first portion of the sequence of a nucleic acid to be detected;
• providing a type of nanoparticles having at least two types of oligonucleotides attached thereto, the first type of oligonucleotides having a sequence complementary to a second portion of the sequence of said nucleic acid, the second type of oligonucleotides having a sequence complementary to at least a portion of the sequence of the oligonucleotides attached to the substrate;
• contacting said nucleic acid, the aggregate probe, the nanoparticles and the substrate, the contacting taking place under conditions effective to allow hybridization of said nucleic acid with the oligonucleotides on the aggregate probe and on the nanoparticles and hybridization of the oligonucleotides on the nanoparticles with the oligonucleotides on the substrate;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• contacting a nucleic acid to be detected with a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the substrate with said nucleic acid;
• contacting said nucleic acid bound to the substrate with liposomes having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the liposomes with said nucleic acid;
• providing an aggregate probe comprising at least two types of nanoparticles having oligonucleotides attached thereto, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of some of the oligonucleotides attached to them, at least one of the types of nanoparticles of the aggregate probe having oligonucleotides attached thereto which have a hydrophobic group attached to the end not attached to the nanoparticles;
• contacting the liposomes bound to the substrate with the aggregate probe under conditions effective to allow attachment of the oligonucleotides on the aggregate probe to the liposomes as a result of hydrophobic interactions;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• providing a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of a nucleic acid to be detected;
• providing a core probe comprising at least two types of nanoparticles, each type of nanoparticles having oligonucleotides attached thereto which are complementary to the oligonucleotides on at least one of the other types of nanoparticles, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of the oligonucleotides attached to them;
• providing a type of nanoparticles having two types of oligonucleotides attached thereto, the first type of oligonucleotides having a sequence complementary to a second portion of the sequence of said nucleic acid, the second type of oligonucleotides having a sequence complementary to a portion of the sequence of the oligonucleotides attached to at least one of the types of nanoparticles of the core probe;
• contacting said nucleic acid, the nanoparticles, the substrate and the core probe under conditions effective to allow hybridization of said nucleic acid with the oligonucleotides on the nanoparticles and with the oligonucleotides on the substrate and to allow hybridization of the oligonucleotides on the nanoparticles with the oligonucleotides on the core probe;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• providing a substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of a nucleic acid to be detected;
• providing a core probe comprising at least two types of nanoparticles, each type of nanoparticles having oligonucleotides attached thereto which are complementary to the oligonucleotides on at least one other type of nanoparticles, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of the oligonucleotides attached to them;
• providing a type of linking oligonucleotides comprising a sequence complementary to a second portion of the sequence of said nucleic acid and a sequence complementary to a portion of the sequence of the oligonucleotides attached to at least one of the types of nanoparticles of the core probe;
• contacting said nucleic acid, the linking oligonucleotides, the substrate and the core probe under conditions effective to allow hybridization of said nucleic acid with the linking oligonucleotides and with the oligonucleotides on the substrate and to allow hybridization of the oligonucleotides on the linking oligonucleotides with the oligonucleotides on the core probe;
• and
• observing a detectable change.

A method of detecting a nucleic acid having at least two portions comprising:

• providing nanoparticles having oligonucleotides attached thereto;
• providing one or more types of binding oligonucleotides, each of the binding oligonucleotides having two portions, the sequence of one portion being complementary to the sequence of one of the portions of the nucleic acid and the sequence of the other portion being complementary to the sequence of the oligonucleotides on the nanoparticles;
• contacting the nanoparticles and the binding oligonucleotides under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with the binding oligonucleotides;
• contacting the nucleic acid and the binding oligonucleotides under conditions effective to allow hybridization of the binding oligonucleotides with the nucleic acid;
• and
• observing a detectable change.

A method of detecting a nucleic acid having at least two portions comprising:

• providing nanoparticles having oligonucleotides attached thereto;
• providing one or more binding oligonucleotides, each of the binding oligonucleotides having two portions, the sequence of one portion being complementary to the sequence of at least two portions of the nucleic acid and the sequence of the other portion being complementary to the sequence of the oligonucleotides on the nanoparticles;
• contacting the nanoparticles and the binding oligonucleotides under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with the binding oligonucleotides;
• contacting the nucleic acid and the binding oligonucleotides under conditions effective to allow hybridization of the binding oligonucleotides with the nucleic acid;
• and
• observing a detectable change.

A method of detecting nucleic acid having at least two portions comprising:

• contacting the nucleic acid with at least two types of particles having oligonucleotides attached thereto,
• the oligonucleotides on the first type of particles having a sequence complementary to a first portion of the sequence of the nucleic acid and being labeled with an energy donor,
• the oligonucleotides on the second type of particles having a sequence complementary to a second portion of the sequence of the nucleic acid and being labeled with an energy acceptor,
• the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the particles with the nucleic acid;
• and
• observing a detectable change brought about by hybridization of the oligonucleotides on the particles with the nucleic acid.

A method of detecting nucleic acid having at least two portions comprising:

• providing a type of microspheres having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of the nucleic acid and being labeled with a fluorescent molecule;
• providing a type of nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a second portion of the sequence of the nucleic acid, nanoparticles being capable of producing a detectable change;
• contacting the nucleic acid with the microspheres and the nanoparticles under conditions effective to allow hybridization of the oligonucleotides on the microspheres and on the nanoparticles with the nucleic acid;
• and
• observing a change in fluorescence, another detectable change produced by the nanoparticles, or both.

A method of detecting nucleic acid having at least two portions comprising:

• providing a first type of metallic or semiconductor nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a first portion of the sequence of the nucleic acid and being labeled with a fluorescent molecule;
• providing a second type of metallic or semiconductor nanoparticles having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to a second portion of the sequence of the nucleic acid and being labeled with a fluorescent molecule;
• contacting the nucleic acid with the two types of nanoparticles under conditions effective to allow hybridization of the oligonucleotides on the two types of nanoparticles with the nucleic acid;
• and
• observing changes in fluorescence.

A method of detecting nucleic acid having at least two portions comprising:

• providing a type of particle having oligonucleotides attached thereto, the oligonucleotides having a first portion and a second portion, both portions being complementary to portions of the sequence of the nucleic acid;
• providing a type of probe oligonucleotides comprising a first portion and a second portion, the first portion having a sequence complementary to the first portion of the oligonucleotides attached to the particles and both portions being complementary to portions of the sequence of the nucleic acid, the probe oligonucleotides further being labeled with a reporter molecule at one end;
• contacting the particle and the probe oligonucleotides under conditions effective to allow for hybridization of the oligonucleotides on the particles with the probe oligonucleotides to produce a satellite probe;
• then contacting the satellite probe with the nucleic acid under conditions effective to provide for hybridization of the nucleic acid with the probe oligonucleotides;
• removing the particles;
• and
• detecting the reporter molecule.

A kit comprising at least three containers:

• the first container holding nanoparticles;
• the second container holding a first oligonucleotide having a sequence complementary to the sequence of a first portion of a nucleic acid;
• and
• the third container holding a second oligonucleotide having a sequence complementary to the sequence of a second portion of the nucleic acid.

A kit comprising:

• a substrate having oligonucleotides attached thereto which have a sequence complementary to the sequence of a first portion of a nucleic acid;
• a first container holding nanoparticles having oligonucleotides attached thereto, some of which have a sequence complementary to the sequence of a second portion of the nucleic acid;
• and
• a second container holding nanoparticles having oligonucleotides attached thereto which have a sequence complementary to at least a portion of the sequence of the oligonucleotides attached to the nanoparticles in the first container.

A kit comprising:

• a substrate;
• a first container holding nanoparticles;
• a second container holding a first oligonucleotide having a sequence complementary to the sequence of a first portion of a nucleic acid;
• a third container holding a second oligonucleotide having a sequence complementary to the sequence of a second portion of the nucleic acid;
• and
• a fourth container holding a third oligonucleotide having a sequence complementary to at least a portion of the sequence of the second oligonucleotide.

A kit comprising:

• a substrate having oligonucleotides attached thereto which have a sequence complementary to the sequence of a first portion of a nucleic acid;
• a first container holding liposomes having oligonucleotides attached thereto which have a sequence complementary to the sequence of a second portion of the nucleic acid;
• and
• a second container holding nanoparticles having at least a first type of oligonucleotides attached thereto, the first type of oligonucleotides having a hydrophobic group attached to the end not attached to the nanoparticles.

A kit comprising:

• a substrate having oligonucleotides attached thereto;
• a first container holding an aggregate probe comprising at least two types of nanoparticles having oligonucleotides attached thereto, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of some of the oligonucleotides attached to them, at least one of the types of nanoparticles of the aggregate probe having oligonucleotides attached thereto which have a sequence complementary to a first portion of the sequence of the nucleic acid;
• and
• a second container holding nanoparticles having at least two types of oligonucleotides attached thereto, the first type of oligonucleotides having a sequence complementary to a second portion of the sequence of the nucleic acid, and the second type of oligonucleotides having a sequence complementary to at least a portion of the sequence of the oligonucleotides attached to the substrate.

A kit comprising:

• a substrate, the substrate having oligonucleotides attached thereto, the oligonucleotides having a sequence complementary to the sequence of a first portion of a nucleic acid;
• a first container holding liposomes having oligonucleotides attached thereto which have a sequence complementary to the sequence of a second portion of the nucleic acid;
• and
• a second container holding an aggregate probe comprising at least two types of nanoparticles having oligonucleotides attached thereto, the nanoparticles of the aggregate probe being bound to each other as a result of the hybridization of some of the oligonucleotides attached to them, at least one of the types of nanoparticles of the aggregate probe having oligonucleotides attached thereto which have a hydrophobic group attached to the end not attached to the nanoparticles.

A kit comprising at least three containers:

• the first container holding nanoparticles;
• the second container holding a first oligonucleotide having a sequence complementary to the sequence of a first portion of a nucleic acid;
• and
• the third container holding a second oligonucleotide having a sequence complementary to the sequence of a second portion of the nucleic acid.

A kit comprising:

• a substrate having oligonucleotides attached thereto which have a sequence complementary to the sequence of a first portion of a nucleic acid;
• a first container holding nanoparticles having oligonucleotides attached thereto, some of which have a sequence complementary to the sequence of a second portion of the nucleic acid;
• and
• a second container holding nanoparticles having oligonucleotides attached thereto which have a sequence complementary to at least a portion of the sequence of the oligonucleotides attached to the nanoparticles in the first container.

A kit comprising:

• a substrate;
• a first container holding nanoparticles;
• a second container holding a first oligonucleotide having a sequence complementary to the sequence of a first portion of a nucleic acid;
• a third container holding a second oligonucleotide having a sequence complementary to the sequence of a second portion of the nucleic acid;
• and
• a fourth container holding a third oligonucleotide having a sequence complementary to at least a portion of the sequence of the second oligonucleotide.

A kit comprising:

• a substrate having oligonucleotides attached thereto which have a sequence complementary to the sequence of a first portion of a nucleic acid;
• a first container holding liposomes having oligonucleotides attached thereto which have a sequence complementary to the sequence of a second portion of the nucleic acid;
• and
• a second container holding nanoparticles having at least a first type of oligonucleotides attached thereto, the first type of oligonucleotides having a hydrophobic group attached to the end not attached to the nanoparticles.

A method of nanofabrication comprising

• providing at least one type of linking oligonucleotide having a selected sequence, the sequence of each type of linking oligonucleotide having at least two portions;
• providing one or more types of nanoparticles having oligonucleotides attached thereto, the oligonucleotides on each of the types of nanoparticles having a sequence complementary to the sequence of a portion of a linking oligonucleotide;
• and
• contacting the linking oligonucleotides and nanoparticles under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles to the linking oligonucleotides so that a desired nanomaterial or nanostructure is formed wherein the nanoparticles are held together by oligonucleotide connectors.

A method of nanofabrication comprising:

• providing at least two types of nanoparticles having oligonucleotides attached thereto,
• the oligonucleotides on the first type of nanoparticles having a sequence complementary to that of the oligonucleotides on the second of the nanoparticles;
• the oligonucleotides on the second type of nanoparticles having a sequence complementary to that of the oligonucleotides on the first type of nanoparticles;
• and
• contacting the first and second types of nanoparticles under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles to each other so that a desired nanomaterial or nanostructure is formed.

An assembly of containers comprising:

• a first container holding nanoparticles having oligonucleotides attached thereto, and
• a second container holding nanoparticles having oligonucleotides attached thereto,
• the oligonucleotides attached to the nanoparticles in the first container having a sequence complementary to that of the oligonucleotides attached to the nanoparticles in the second container,
• the oligonucleotides attached to the nanoparticles in the second container having a sequence complementary to that of the oligonucleotides attached to the nanoparticles in the second container.

A method of binding oligonucleotides to charged nanoparticles to produce stable nanoparticle-oligonucleotide conjugates, the method comprising:

• providing oligonucleotides having covalently bound thereto a moiety comprising a functional group which can bind to the nanoparticles;
• contacting the oligonucleotides and the nanoparticles in water for a period of time sufficient to allow at least some of the oligonucleotides to bind to the nanoparticles;
• adding at least one salt to the water to form a salt solution, the ionic strength of the salt solution being sufficient to overcome at least partially the electrostatic attraction or repulsion of the oligonucleotides for the nanoparticles and the electrostatic repulsion of the oligonucleotides for each other;
• and
• contacting the oligonucleotides and nanoparticles in the salt solution for an additional period of time sufficient to allow sufficient additional oligonucleotides to bind to the nanoparticles to produce the stable nanoparticle-oligonucleotide conjugates.

A method of binding oligonucleotides to nanoparticles to produce nanoparticle-oligonucleotide conjugates, the method comprising:

• providing oligonucleotides, the oligonucleotides comprising:
• a type of recognition oligonucleotides;
• and
• a type of diluent oligonucleotides;
• contacting the oligonucleotides with the nanoparticles under conditions effective to allow at least some of each of the types of oligonucleotides to bind to the nanoparticles to produce the nanoparticle-oligonucleotide conjugates.

A method of binding oligonucleotides to charged nanoparticles to produce nanoparticle-oligonucleotide conjugates, the method comprising:

• providing oligonucleotides having covalently bound thereto a moiety comprising a functional group which can bind to the nanoparticles, the oligonucleotides comprising:
• a type of recognition oligonucleotides;
• and
• a type of diluent oligonucleotides;
• contacting the oligonucleotides with the nanoparticles in water for a period of time sufficient to allow at least some of each of the types of oligonucleotides to bind to the nanoparticles;
• adding at least one salt to the water to form a salt solution, the ionic strength of the salt solution being sufficient to overcome at least partially the electrostatic attraction or repulsion of the oligonucleotides for the nanoparticles and the electrostatic repulsion of the oligonucleotides for each other;
• and
• contacting the oligonucleotides and nanoparticles in the salt solution for an additional period of time sufficient to allow additional oligonucleotides of each of the types of oligonucleotides to bind to the nanoparticles to produce the nanoparticle-oligonucleotide conjugates.

A method of detecting a nucleic acid having at least two portions comprising:

• (a) contacting the nucleic acid with a substrate having oligonucleotides attached thereto, the oligonucleotides being located between a pair of electrodes, the oligonucleotides having a sequence complementary to a first portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the substrate with said nucleic acid;
• (b) contacting said nucleic acid bound to the substrate with a first type of nanoparticles, the nanoparticles being made of a material which can conduct electricity, the nanoparticles having one or more types of oligonucleotides attached thereto, at least one of the types of oligonucleotides having a sequence complementary to a second portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with said nucleic acid;
• and
• (c) detecting a change in conductivity.

A method of detecting nucleic acid having at least two portions comprising:

• (a) contacting a nucleic acid with a substrate having oligonucleotides attached thereto, the oligonucleotides being located between a pair of electrodes, the oligonucleotides having a sequence complementary to a first portion of the sequence of said nucleic acid, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the substrate with said nucleic acid;
• (b) contacting said nucleic acid bound to the substrate with an aggregate probe having oligonucleotides attached thereto, at least one of the types of oligonucleotides on the aggregate probe comprising a sequence complementary to the sequence of a second portion of said nucleic acid, the nanoparticles of the aggregate probe being made of a material which can conduct electricity, the contacting taking place under conditions effective to allow hybridization of the oligonucleotides on the aggregate probe with the nucleic acid;
• and
• (c) detecting a change in conductivity.