Particle-mediated delivery of biologics

Abstract

A composition for delivering a biologic to a subject generally includes a particulate substrate and an mRNA encapsulated by the particulate substrate. In some cases, the mRNA bay be indirectly attached to the particulate substrate. The mRNA encodes at least one therapeutic polypeptide. The composition may be delivered to a tissue of a subject to provide a therapeutic benefit to the tissue.

1 . A method for improving cardiac function in a mammal, the method comprising:
 administering to the mammal a composition comprising a particle encapsulating an mRNA, the mRNA encoding a polypeptide useful for regenerating cardiac function or regenerating tissue, thereby improving cardiac function of the mammal.   
     
     
         2 . The method of  claim 1 , wherein the polypeptide is NAP-2, TGF-α, ErBb3, VEGF, IGF-1, FGF-2, PDGF, IL-2, CD19, CD20, or CD80/86. 
     
     
         3 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         4 . The method of  claim 3 , wherein the human has undergone percutaneous coronary intervention for ST-elevation myocardial infarction. 
     
     
         5 . The method of  claim 1 , wherein the composition is administered to the mammal by arterial administration. 
     
     
         6 . The method of  claim 1 , wherein the particle comprises alginate. 
     
     
         7 . The method of  claim 6 , wherein the alginate is in the form of an alginate gel. 
     
     
         8 . The method of  claim 7 , wherein the alginate gel comprises a calcium salt. 
     
     
         9 . The method of  claim 8 , wherein the alginate gel has a ratio of alginate to calcium salt can be from about 2:1 to about 10:1. 
     
     
         10 . The method of  claim 1 , wherein the particle is from about 5 μm to about 10 μm in diameter. 
     
     
         11 . The method of  claim 1 , wherein the particle is a biphasic particle. 
     
     
         12 . The method of  claim 11 , wherein the biphasic particle is a polarized particle. 
     
     
         13 . The method of  claim 11 , wherein the biphasic particle comprises a tail. 
     
     
         14 . The method of  claim 1 , wherein the method comprises administering the composition during a percutaneous coronary intervention. 
     
     
         15 . The method of  claim 1 , where the particle further comprises a scaffold protein. 
     
     
         16 . The method of  claim 15 , where the scaffold protein is selected from the group consisting of collagen I, collagen II, collagen III, collagen IV, fibrin, and gelatin. 
     
     
         17 . The method of  claim 1 , where the particle further encapsulates a polypeptide. 
     
     
         18 . The method of  claim 17 , where the polypeptide is an antibody having the ability to neutralize tumor necrosis factor activity, an antibody having the ability to neutralize mitochondrial complex-1 activity, or a resolvin-D1 agonist. 
     
     
         19 . The method of  claim 1 , where the particle further encapsulates a lipopolysaccharide. 
     
     
         20 . The method of  claim 1 , wherein the particle further encapsulates a microvesicle and/or exosome. 
     
     
         21 . A method for improving cardiac function in a mammal, the method comprising: administering to the mammal composition comprising a particle encapsulating an inhibitory RNA, the inhibitory RNA reducing expression of a polypeptide in which reduced expression of the polypeptide improves cardiac function, thereby improving cardiac function of the mammal, wherein the polypeptide is eotaxin-3, cathepsin-S, DK-1, follistatin, ST-2, GRO-a, IL-21, NOV, transferrin, TIMP-2, TNFaRI, TNFaRII, angiostatin, CCL25, ANGPTL4, or MMP-3. 
     
     
         22 . The method of  claim 21 , wherein the mammal is a human. 
     
     
         23 . The method of  claim 22 , wherein the human has undergone percutaneous coronary intervention for ST-elevation myocardial infarction. 
     
     
         24 . The method of  claim 21 , wherein the composition is administered to the mammal by arterial administration. 
     
     
         25 . The method of  claim 21 , wherein the particle comprises alginate. 
     
     
         26 . The method of  claim 25 , wherein the alginate is in the form of an alginate gel. 
     
     
         27 . The method of  claim 26 , wherein the alginate gel comprises a calcium salt. 
     
     
         28 . The method of  claim 27 , wherein the alginate gel has a ratio of alginate to calcium salt can be from about 2:1 to about 10:1. 
     
     
         29 . The method of  claim 21 , wherein the particle is from about 5 μm to about 10 μm in diameter. 
     
     
         30 . The method of  claim 21 , wherein the particle is a biphasic particle. 
     
     
         31 . The method of  claim 30 , wherein the biphasic particle is a polarized particle. 
     
     
         32 . The method of  claim 30 , wherein the biphasic particle comprises a tail. 
     
     
         33 . The method of  claim 21 , wherein the method comprises administering the composition during a percutaneous coronary intervention. 
     
     
         34 . The method of  claim 21 , where the particle further comprises a scaffold protein. 
     
     
         35 . The method of  claim 34 , where the scaffold protein is selected from the group consisting of collagen I, collagen II, collagen III, collagen IV, fibrin, and gelatin. 
     
     
         36 . The method of  claim 21 , where the particle further encapsulates a polypeptide. 
     
     
         37 . The method of  claim 36 , where the polypeptide is selected from the group consisting of an antibody having the ability to neutralize tumor necrosis factor activity, an antibody having the ability to neutralize mitochondrial complex-1 activity, and a resolvin-D1 agonist. 
     
     
         38 . The method of  claim 21 , where the particle further encapsulates a lipopolysaccharide. 
     
     
         39 . The method of  claim 21 , wherein the particle further encapsulates a microvesicle and/or exosome. 
     
     
         40 . A composition comprising:
 a particulate substrate;   an mRNA attached to the particulate substrate, the mRNA comprising at least one modification to inhibit degradation of the mRNA when the mRNA is in cytosol of a cell, the mRNA encoding at least one therapeutic polypeptide.   
     
     
         41 . The composition of  claim 40 , wherein the mRNA modification comprises a pseudoknot, an RNA stability element, or an artificial 3′ stem loop. 
     
     
         42 . The composition of  claim 40 , wherein the particulate substrate comprises a surface modification. 
     
     
         43 . The composition of  claim 42 , wherein the surface modification comprises a biocompatible polymer. 
     
     
         44 . The composition of  claim 43 , wherein the biocompatible polymer comprises polyethylene glycol (PEG). 
     
     
         45 . The composition of  claim 44 , wherein the biocompatible polymer comprises chitosan. 
     
     
         46 . The composition of  claim 40 , wherein the particulate substrate comprises a nanoparticle. 
     
     
         47 . The composition of  claim 40 , wherein the particulate substrate comprises a microparticle. 
     
     
         48 . The composition of  claim 40 , wherein the particulate substrate comprises a plurality of nanoparticles. 
     
     
         49 . The composition of  claim 48 , wherein the plurality of nanoparticles comprises:
 at least one nanoparticle comprising from a first material; and   at least one nanoparticle comprising a second material.   
     
     
         50 . The composition of  claim 40 , wherein the therapeutic polypeptide comprises:
 an immunoglobulin heavy chain; or   an immunoglobulin light chain.