METHODS, COMPOSITIONS, AND SYSTEMS FOR DELIVERING THERAPEUTIC AND DIAGNOSTIC AGENTS INTO CELLS

1 - 272 . (canceled)

273 . A pH-sensitive, membrane-destabilizing polymer, wherein the pH-sensitive polymer is a random block copolymer of formula II:

T1-L-[PEGMA m -PDSMA n -BPAM p ] v -[DMAEMA q -PAA r -BMA s ] w   II

wherein

PEGMA is a polyethylene glycol methacrylate residue with 2-20 ethylene glycol units;

PDSMA is pyridyl disulfide methacrylate residue;

BPAM is 2-[2-Boc amino ethoxy]ethyl methacrylate residue;

BMA is butyl methacrylate residue;

PAA is propyl acrylic acid residue;

DAEMA is dimethylaminoethyl methacrylate residue;

m is a mole fraction of 0.6 to 1;

n is a mole fraction of greater than 0;

p is a mole fraction of 0;

m

+

n

+

p

=

1

q is a mole fraction of 0.2 to 0.75;

r is a mole fraction of 0.05 to 0.6;

s is a mole fraction of 0.2 to 0.75;

q

+

r

+

s

=

1

v is 1 to 25 kDa;

w is 1 to 25 kDa;

T1 is a first targeting ligand; and

L is absent or is a linking moiety.

274 . The polymer of claim 273 , wherein PEGMA is polyethyleneglycol methacrylate residue having 4-5 ethylene glycol units or 7-8 ethylene glycol units.

275 . The polymer of claim 273 , wherein L is a linking moiety.

276 . The polymer of claim 275 , wherein L includes a polyethylene glycol (PEG) moiety having 2-20 ethylene glycol units.

277 . The polymer of claim 273 , wherein T1 comprises an N-acetylgalactosamine (NAG) residue.

278 . The polymer of claim 277 , wherein T1 is

279 . The polymer of claim 273 , wherein the compound of formula II is a compound of formula IIa:

NAG-PEG 12 -[PEGMA300 m -PDSMA n ] v -[D q -P r —B s ] w   IIa

wherein

NAG is an N-acetylgalactosamine residue;

PEG 12 is a linking moiety comprising a polyethylene glycol having 12 ethylene glycol units;

D is a butyl methacrylate residue (DMAEMA);

P is a propyl acrylic acid residue (PAA);

B is a butyl methacrylate residue (BMA); and

m, n, q, r, s, v, and w are as defined in claim 273 .

280 . The polymer of claim 279 , wherein

m is from 0.85 to 0.9,

n is from 0.1 to 0.15,

q is from 0.33 to 0.37,

r is from 0.07 to 0.15,

s is from 0.52 to 0.57,

v is from 3 kDa to 4.5 kDa, and

w is from 5.5 kDa to 7 kDa.

281 . The polymer of claim 273 , wherein the polymer is covalently bound to a polynucleotide.

282 . The polymer of claim 281 , wherein the polynucleotide comprises from 7 nucleotide monomeric units to 20,000 nucleotide monomeric units.

283 . The polymer of claim 281 , wherein the polynucleotide is single stranded or double stranded.

284 . The polymer of claim 281 , wherein the polynucleotide is a deoxyribonucleic acid (DNA), a ribonucleic acid (RNA), or a derivative of the DNA or the RNA, or a combination thereof.

285 . The polymer of claim 284 , wherein the RNA is in the form of in vitro polymerized RNA, external guide sequences, small non-messenger RNAs (snmRNA), untranslated RNA (utRNA), or derivatives thereof.

286 . The polymer of claim 281 , wherein the polynucleotide is an oligonucleotide comprising less than 200 nucleotide monomeric units.

287 . The polymer of claim 286 , where the oligonucleotide is selected from the group consisting of an siRNA, an antisense oligonucleotide, a dicer substrate, a miRNA, an aiRNA, and an shRNA.

288 . The polymer of claim 281 , wherein the polynucleotide comprises one or more modified nucleotides, wherein said one or more modified nucleotides have been modified relative to naturally occurring nucleotides.

289 . The polymer of claim 288 , wherein said one or more modified nucleotides comprise one or more alterations in sugar moieties or in pyrimidine or purine base moieties, or said one or more modified nucleotides comprise one or more alterations in both sugar moieties and in pyrimidine or purine base moieties.

290 . A pharmaceutical composition, comprising a pH-sensitive, membrane-destabilizing polymer of claim 273 and a pharmaceutically acceptable carrier.