RELEASABLE FUSOGENIC LIPIDS FOR NUCLEIC ACIDS DELIVERY SYSTEMS

1 . A compound of Formula (I):

R-(L 1 ) a -M-(L 2 ) b -Q   (I)

wherein

R is a water soluble neutral charged or zwitterion-containing moiety;

L 1-2 are independently selected bifunctional linkers;

M is an imine-containing moiety;

Q is a substituted or unsubstituted, saturated or unsaturated C4-30-containing moiety;

(a) is 0 or a positive integer; and

(b) is 0 or a positive integer.

2 . The compound of claim 1 , wherein M is —N═CR 1 — or —CR 1 ═N—, wherein R 1 is hydrogen, C 1-6 alkyl, C 3-8 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 3-8 substituted cycloalkyl, aryl and substituted aryl.

3 . The compound of claim 1 , wherein the zwitterion-containing moiety includes an amine and an acid, wherein the acidic proton is positioned three to eight atoms from the amine, and the acid is a carboxylic acid, a sulfonic acid, or a phosphoric acid.

4 . (canceled)

5 . The compound of claim 3 , wherein the zwitterion-containing moiety is a zwitterionic form of an amino acid.

6 . The compound of claim 1 , wherein Q has Formula (Ia):

wherein

Y 1 and Y′ 1 are independently O, S or NR 4 ;

(c) is 0 or 1;

(d) is 0 or a positive integer;

(e) is 0 or 1;

X is C, N or P;

Q 1 is H, C 1-3 alkyl, NR 5 , OH, or

Q 2 is H, C 1-3 alkyl, NR 6 , OH, or

Q 3 is a lone electron pair, (═O), H, C 1-3 alkyl, NR 7 , OH, or

provided that

(i) when X is C, Q 3 is not a lone electron pair or (═O);

(ii) when X is N, Q 3 is a lone electron pair; and

(iii) when X is P, Q 3 is (═O) and (e) is zero,

wherein

L 11 , L 12 and L 13 are independently selected bifunctional spacers;

Y 11 , Y′ 11 , Y 12 , Y′ 12 , Y 13 , and Y′ 13 are independently O, S or NR 8 ;

R 11 , R 12 and R 13 are independently substituted or unsubstituted, saturated or unsaturated C 4-30 ;

(f1), (f2) and (f3) are independently 0 or 1;

(g1), (g2) and (g3) are independently 0 or 1; and

(h1), (h2) and (h3) are independently 0 or 1;

R 2-3 are independently selected from the group consisting of hydrogen, hydroxyl, amine, substituted amine, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 2-6 substituted alkenyl, C 2-6 substituted alkynyl, C 3-8 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroalkyl, and substituted C 1-6 heteroalkyl; and

R 4-8 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 2-6 substituted alkenyl, C 2-6 substituted alkynyl, C 3-8 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1-6 heteroalkyl, and substituted C 1-6 heteroalkyl,

provided that Q includes at least one or two of R 11 , R 12 and R 13 .

7 . The compound of claim 6 , having Formula (Ib) or (I′b):

8 . The compound of claim 6 , wherein Q 1-3 independently include groups selected from C12-22 alkyl, C12-22 alkenyl, C12-22 alkyloxy, auroyl (C12), myristoyl (C14), palmitoyl (C16), stearoyl (C18), oleoyl (C18), and erucoyl (C22); saturated or unsaturated C12 alkyloxy, C14 alkyloxy, C16 alkyloxy, C18 alkyloxy, C20 alkyloxy, and C22 alkyloxy; and saturated or unsaturated C12 alkyl, C14 alkyl, C16 alkyl, C18 alkyl, C20 alkyl and C22 alkyl.

9 . The compound of claim 6 , wherein L 11 , L 12 and L 13 are independently selected from the group consisting of:

—(CR 31 R 32 ) q1 —,

—Y 26 (CR 31 R 32 ) q1 —,

—CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —O(CH 2 ) 2 —, —O(CH 2 ) 3 —, —O(CH 2 ) 4 —, —O(CH 2 ) 5 —, —O(CH 2 ) 6 —, and CH(OH)—,

wherein:

Y 26 is O, NR 33 , or S;

R 31-32 are independently selected from the group consisting of hydrogen, hydroxyl, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

R 33 is selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; and

(q1) is zero or a positive integer.

10 . (canceled)

11 . The compound of claim 1 , wherein L 1 is selected from the group consisting of:

—(CR 21 R 22 ) t1 —[C(═Y 16 )] a3 —,

—(CR 21 R 22 ) t1 Y 17 —(CR 23 R 24 ) t2 —(Y 18 ) a2 —[C(═Y 16 )] a3 —,

—(CR 21 R 22 CR 23 R 24 Y 17 ) t1 —[C(═Y 16 )] a3 —,

—(CR 21 R 22 CR 23 R 24 Y 17 ) t1 (CR 25 R 26 ) t4 —(Y 18 ) a2 —[C(═Y 16 )] a3 —,

—[(CR 21 R 22 CR 23 R 24 ) t2 Y 17 ] t3 (CR 25 R 26 ) t4 —(Y 18 ) a2 —[C(═Y 16 )] a3 —,

—(CR 21 R 22 ) t1 —[(CR 23 R 24 ) t2 Y 17 ] t3 (CR 25 R 26 ) t4 ≦(Y 18 ) a2 —[C(═Y 16 )] a3 —,

—(CR 21 R 22 ) t1 (Y 17 ) a2 [C(═Y 16 )] a3 (CR 23 R 24 ) t2 —,

—(CR 21 R 22 ) t1 (Y 17 ) a2 [C(═Y 16 )] a3 Y 14 (CR 23 R 24 ) t2 —,

—(CR 21 R 22 ) t1 (Y 17 ) a2 [C(═Y 16 )] a3 (CR 23 R 24 ) t2 —Y 15 —(CR23R 24 ) t3 —,

—(CR 21 R 22 ) t1 (Y 17 ) a2 [C(═Y 16 )] a3 Y 14 (CR 23 R 24 ) t2 —Y 15 —(CR 23 R 24 ) t3 —,

—(CR 21 R 22 ) t1 (Y 17 ) a2 [C(═Y 16 )] a3 (CR 23 R 24 CR 25 R 26 Y 19 ) t2 (CR 27 CR 28 ) t3 —,

—(CR 21 R 22 ) t1 (Y 17 ) a2 [C(═Y 16 )] a3 Y 14 (CR 23 R 24 CR 25 R 26 Y 19 ) t2 (CR 27 CR 28 ) t3 —,

—CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —NH(CH 2 )—,

—CH(NH 2 )CH 2 —,

—(CH 2 ) 4 —C(═O)—, —(CH 2 ) 5 —C(═O)—, —(CH 2 ) 6 —C(═O)—,

—CH 2 CH 2 O—CH 2 O—C(═O)—,

—(CH 2 CH 2 O) 2 —CH 2 O—C(═O)—,

—(CH 2 CH 2 O) 3 —CH 2 O—C(═O)—,

—(CH 2 CH 2 O) 2 —C(═O)—,

—CH 2 CH 2 O—CH 2 CH 2 NH—C(═O)—,

—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—C(═O)—,

—CH 2 —O—CH 2 CH 2 O—CH 2 CH 2 NH—C(═O)—,

—CH 2 —O—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—C(═O)—,

—CH 2 —O—CH 2 CH 2 O—CH 2 C(═O)—,

—CH 2 —O—(CH 2 CH 2 O) 2 —CH 2 C(═O)—,

—(CH 2 ) 4 —C(═O)NH—, —(CH 2 ) 5 —C(═O)NH—,

—(CH 2 ) 6 —C(═O)NH—,

—CH 2 CH 2 O—CH 2 O—C(═O)—NH—,

—(CH 2 CH 2 O) 2 —CH 2 O—C(═O)—NH—,

—(CH 2 CH 2 O) 3 —CH2O—C(═O)—NH—,

—(CH 2 CH 2 O) 2 —C(═O)—NH—,

—CH 2 CH 2 O—CH 2 CH 2 NH—C(═O)—NH—,

—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—C(═O)—NH—,

—CH 2 —O—CH 2 CH 2 O—CH 2 CH 2 NH—C(═O)—NH—,

—CH 2 —O—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—C(═O)—NH—,

—CH 2 —O—CH 2 CH 2 O—CH 2 C(═O)—NH—,

—CH 2 —O—(CH 2 CH 2 O) 2 —CH 2 C(═O)—NH—,

—(CH 2 CH 2 O) 2 —, —CH 2 CH 2 O—CH 2 O—,

—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—,

—(CH 2 CH 2 O) 3 —CH 2 CH 2 NH—,

—CH 2 CH 2 O—CH 2 CH 2 NH—,

—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—,

—CH 2 —O—CH 2 CH 2 O—CH 2 CH 2 NH—,

—CH 2 —O—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—,

—CH 2 —O—CH 2 CH 2 O—,

—CH 2 —O—(CH 2 CH 2 O) 2 —,

—C(═O)NH(CH 2 ) 2 —, —CH 2 C(═O)NH(CH 2 ) 2 —,

—C(═O)NH(CH 2 ) 3 —, —CH 2 C(═O)NH(CH 2 ) 3 —,

—C(═O)NH(CH 2 ) 4 —, —CH 2 C(═O)NH(CH 2 ) 4 —,

—C(═O)NH(CH 2 ) 5 —, —CH 2 C(═O)NH(CH 2 ) 5 —,

—C(═O)NH(CH 2 ) 6 —, —CH 2 C(═O)NH(CH 2 ) 6 —,

—C(═O)O(CH 2 ) 2 —, —CH 2 C(═O)O(CH 2 ) 2 —,

—C(═O)O(CH 2 ) 3 —, —CH 2 C(═O)O(CH 2 ) 3 —,

—C(═O)O(CH 2 ) 4 —, —CH 2 C(═O)O(CH 2 ) 4 —,

—C(═O)O(CH 2 ) 5 —, —CH 2 C(═O)O(CH 2 ) 5 —,

—C(═O)O(CH 2 ) 6 —, —CH 2 C(═O)O(CH 2 ) 6 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 2 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 3 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 4 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 5 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 6 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 2 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 3 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 4 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 5 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 6 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 2 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 3 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 4 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 5 —, and

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 6 —,

wherein:

Y 16 is O, NR 28 , or S;

Y 14-15 and Y 17-19 are independently O, NR 29 , or S;

R 21-27 are independently selected from the group consisting of hydrogen, hydroxyl, amine, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; and

R 28-29 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

(t1), (t2), (t3) and (t4) are independently zero or positive integers; and

(a2) and (a3) are independently zero or 1.

12 . (canceled)

13 . The compound of claim 1 , wherein L 2 is selected from the group consisting of:

—(CR′ 21 R′ 22 ) t′1 —[C(═Y′ 16 )] a′3 (CR′ 27 CR′ 28 ) t′2 —,

—(CR′ 21 R′ 22 ) t′1 Y′ 14 —(CR′ 23 R′ 24 ) t′2 —(Y′ 15 ) a′2 —[C(═Y′ 16 )] n′3 (CR′ 27 CR′ 28 ) t′3 —,

—(CR′ 21 R′ 22 CR′ 23 R′ 24 Y′ 14 ) t+1 —[C(═Y′ 16 )] a′3 (CR′ 27 CR′ 28 ) t′2 —,

—(CR′ 21 R′ 22 CR′ 23 R′ 24 Y′ 14 ) t′1 (CR′ 25 R′ 26 ) t′2 —(Y′ 15 ) a′2 —[C(═Y′ 16 )] a′3 (CR′ 27 CR′ 28 ) t′3 —,

—[(CR′ 21 R′ 22 CR′ 23 R′ 24 ) t′2 Y′ 14 ] t′1 (CR′ 25 R′ 26 ) t′2 —(Y′ 15 ) a′2 —[C(═Y′ 16 )] a′3 (CR′ 27 CR′ 28 ) t′3 —,

—(CR′ 21 R′ 22 ) t′1 —[(CR′ 23 R′ 24 ) t′2 Y′ 14 ] t′2 (CR′ 25 R′ 26 ) t′3 —(Y′ 15 ) a′2 —[C(═Y′ 16 )] a′3 (CR′ 27 CR′ 28 ) t′4 —

—(CR′ 21 R′ 22 ) t′1 (Y′ 14 ) a′2 [C(═Y′ 16 )] a′3 (CR′ 23 R′ 24 ) t′2 —,

—(CR′ 21 R′ 22 ) t′1 (Y′ 14 ) a′2 [C(═Y′ 16 )] a′3 (CR′ 23 R′ 24 ) t′2 —,

—(CR′ 21 R′ 22 ) t′1 (Y′ 14 ) a′2 [C(═Y′ 16 )] a′3 (CR′ 23 R′ 24 ) t′2 —Y′ 15 —(CR′ 23 R′ 24 ) t′3 —,

—(CR′ 21 R′ 22 ) t′1 (Y′ 14 ) a′2 [C(═Y′ 16 )] a′3 (CR′ 23 R′ 24 ) t′2 —Y′ 15 —(CR′ 23 R′ 24 ) t′3 —,

—(CR′ 21 R′ 22 ) t′1 (Y′ 14 ) a′2 [C(═Y′ 16 )] a′3 (CR′ 23 R′ 24 CR′ 25 R′ 26 Y′ 15 ) t′2 (CR′ 27 CR′ 28 ) t′3 —,

—(CR′ 21 R′ 22 ) t′1 (Y′ 14 ) a′2 [C(═Y′ 16 )] a′3 (CR′ 23 R′ 24 CR′ 25 R′ 26 Y′ 15 ) t′2 (CR′ 27 CR′ 28 ) t′3 —,

—CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —,—(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —NH(CH 2 )—,

—CH(NH 2 )CH 2 —,

—O(CH 2 ) 2 —, —C(═O)O(CH 2 ) 3 —, —C(═O)NH(CH 2 ) 3 —,

—C(═O)O(CH 2 ) 2 , —C(═O)(CH 2 ) 3 —,

—CH 2 —C(═O)—O(CH 2 ) 3 —,

—CH 2 —C(═O)—NH(CH 2 ) 3 —,

—CH 2 —OC(═O)—O(CH 2 ) 3 —,

—CH 2 —OC(═O)—NH(CH 2 ) 3 —,

—(CH 2 ) 2 —C(═O)—O(CH 2 ) 3 —,

—(CH 2 ) 2 )—C(═O)—NH(CH 2 ) 3 —,

—CH 2 C(═O)O(CH 2 ) 2 —O—(CH 2 ) 2 —,

—CH 2 C(═O)NH(CH 2 ) 2 —O—(CH 2 ) 2 —,

—(CH 2 ) 2 C(═O)O(CH 2 ) 2 —O—(CH 2 ) 2 —,

—(CH 2 ) 2 C(═O)NH(CH 2 ) 2 —O—(CH 2 ) 2 —,

—CH 2 C(═O)O(CH 2 CH 2 O) 2 CH 2 CH 2 —,

—(CH 2 ) 2 C(═O)O(CH 2 CH 2 O) 2 CH 2 CH 2 —,

—(CH 2 CH 2 O) 2 —, —CH 2 CH 2 O—CH 2 O—,

—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—, —(CH 2 CH 2 O) 3 —CH 2 CH 2 NH—,

—CH 2 CH 2 O—CH 2 CH 2 NH—,

—CH 2 —O—CH 2 CH 2 O—CH 2 CH 2 NH—,

—CH 2 —O—(CH 2 CH 2 O) 2 —CH 2 CH 2 NH—,

—CH 2 —O—CH 2 CH 2 O—, —CH 2 —O—(CH 2 CH 2 O) 2 —,

—(CH 2 ) 2 NHC(═O)—(CH 2 CH 2 O) 2 —,

—C(═O)NH(CH 2 ) 2 —, —CH 2 C(═O)NH(CH 2 ) 2 —,

—C(═O)NH(CH 2 ) 3 —, —CH 2 C(═O)NH(CH 2 ) 3 —,

—C(═O)NH(CH 2 ) 4 —, —CH 2 C(═O)NH(CH 2 ) 4 —,

—C(═O)NH(CH 2 ) 5 —, —CH 2 C(═O)NH(CH 2 ) 5 —,

—C(═O)NH(CH 2 ) 6 —, —CH 2 C(═O)NH(CH 2 ) 6 —,

—C(═O)O(CH 2 ) 2 —, —CH 2 C(═O)O(CH 2 ) 2 —,

—C(═O)O(CH 2 ) 3 —, —CH 2 C(═O)O(CH 2 ) 3 —,

—C(═O)O(CH 2 ) 4 —, —CH 2 C(═O)O(CH 2 ) 4 —,

—C(═O)O(CH 2 ) 5 —, —CH 2 C(═O)O(CH 2 ) 5 —,

—C(═O)O(CH 2 ) 6 —, —CH 2 C(═O)O(CH 2 ) 6 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 2 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 3 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 4 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 5 —,

—(CH 2 CH 2 ) 2 NHC(═O)NH(CH 2 ) 6 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 2 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 3 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 4 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 5 —,

—(CH 2 CH 2 ) 2 NHC(═O)O(CH 2 ) 6 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 2 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 3 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 4 —,

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 5 —, and

—(CH 2 CH 2 ) 2 NHC(═O)(CH 2 ) 6 —,

wherein:

Y′ 16 is O, NR′ 28 , or S;

Y′ 14-15 and Y′ 17 are independently O, NR′ 29 , or S;

R′ 21-27 are independently selected from the group consisting of hydrogen, hydroxyl, amine, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

R′ 28-29 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

(t′1), (t′2), (t′3) and (t′4) are independently zero or positive integers; and

(a′2) and (a′3) are independently zero or 1.

14 . (canceled)

15 . The compound of claim 1 , wherein Q is selected from the group consisting of:

wherein

Y 1 is O, S, or NR 31 ;

R 11 , R 12 , and R 13 are independently selected from the group consisting of substituted or unsubstituted, saturated or unsaturated C 4-30 , the same or different C12-22 saturated or unsaturated aliphatic hydrocarbons;

R 31 is hydrogen, methyl or ethyl;

(d) is 0 or a positive integer; and

(f11), (f12) and (f13) are independently 0, 1, 2, 3, or 4; and

(f21) and (f22) are independently 1, 2, 3 or 4.

16 . (canceled)

17 . The compound of claim 1 selected from the group consisting of:

18 . A nanoparticle composition comprising a compound of Formula (I) of claim 1 .

19 . The nanoparticle composition of claim 18 , wherein the compound of Formula (I) is

20 . The nanoparticle composition of claim 18 , further comprising a cationic lipid, and a PEG-lipid.

21 . The nanoparticle composition of claim 20 , wherein the cationic lipid is

22 . The nanoparticle composition of claim 20 , wherein the PEG lipid is selected from the group consisting of PEG-DSPE, PEG-dipalmitoylglycamide, C16mPEG-ceramide and combinations thereof.

23 . The nanoparticle composition of claim 20 , further comprising cholesterol.

24 . The nanoparticle composition of claim 20 , wherein the cationic lipid has a molar ratio ranging from about 10% to about 99.9% of the total lipid present in the nanoparticle composition.

25 . (canceled)

26 . The nanoparticle composition of claim 24 , wherein a molar ratio of a cationic lipid, a fusogenic lipid including a compound of Formula (I), a PEG-lipid, and cholesterol is about 15-25%:20-78%:0-50%:2-10%: of the total lipid present in the nanoparticle composition.

27 . The nanoparticle composition of claim 18 comprising nucleic acids encapsulated with the nanoparticle composition.

28 . The nanoparticle of claim 27 , wherein the nucleic acids is a single stranded or double stranded oligonucleotide.

29 . The nanoparticle of claim 27 , wherein the nucleic acids are selected from the group consisting of deoxynucleotide, ribonucleotide, locked nucleic acids (LNA), short interfering RNA (siRNA), microRNA (miRNA), aptamers, peptide nucleic acid (PNA), phosphorodiamidate morpholino oligonucleotides (PMO), tricyclo-DNA, double stranded oligonucleotide (decoy ODN), catalytic RNA (RNAi), aptamers, spiegelmers, CpG oligomers and combinations thereof.

30 .- 33 . (canceled)

34 . The nanoparticle of claim 28 , wherein the oligonucleotide inhibits expression of oncogenes, pro-angiogenesis pathway genes, pro-cell proliferation pathway genes, viral infectious agent genes, and pro-inflammatory pathway genes.

35 . The nanoparticle of claim 28 , wherein the oligonucleotide is selected from the group consisting of antisense bcl-2 oligonucleotides, antisense HIF-1α oligonucleotides, antisense survivin oligonucleotides, antisense ErbB3 oligonucleotides, antisense PIK3CA oligonucleotides, antisense HSP27 oligonucleotides, antisense androgen receptor oligonucleotides, antisense Gli2 oligonucleotides, and antisense beta-catenin oligonucleotides.

36 . The nanoparticle of claim 28 , wherein the oligonucleotide comprises eight or more consecutive nucleotides set forth in SEQ ID NO: 1, SEQ ID NOs 2 and 3, SEQ ID NO:4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, and each nucleic acid is a naturally occurring or modified nucleic acid.

37 . The nanoparticle of claim 27 , wherein the charge ratio of the nucleic acids and the compound of Formula (I) ranges from about 1:20 to about 20:1.

38 . The nanoparticle of claim 27 , wherein the nanoparticle has a size ranging from about 50 nm to about 150 nm.

39 .- 40 . (canceled)

41 . A method of inhibiting or downregulating a gene expression in human cells or tissues, comprising:

contacting human cells or tissues with a nanoparticle of claim 27 .

42 . The method of claim 41 , wherein the cells or tissues are cancer cells or tissues.

43 . (canceled)

44 . A method of inhibiting the growth or proliferation of cancer cells comprising:

contacting a cancer cell with a nanoparticle of claim 27 .

45 . The method of claim 44 , further comprising administering an anticancer agent.