title: Virus-mimetic polyplex particles for systemic and inflammation-specific targeted delivery of large genetic contents.
abstract: Systemic and target-specific delivery of large genetic contents has been difficult to achieve. Although viruses effortlessly deliver kilobase-long genome into cells, its clinical use has been hindered by serious safety concerns and the mismatch between native tropisms and desired targets. Nonviral vectors, in contrast, are limited by low gene transfer efficiency and inherent cytotoxicity. Here we devised virus-mimetic polyplex particles (VMPs) based on electrostatic self-assembly among polyanionic peptide (PAP), cationic polymer polyethyleneimine (PEI) and nucleic acids. We fused PAP to the engineered ligand-binding domain of integrin αLβ2 to target intercellular adhesion molecule-1 (ICAM-1), an inducible marker of inflammation. Fully assembled VMPs packaged large genetic contents, bound specifically to target molecules, elicited receptor-mediated endocytosis and escaped endosomal pathway, resembling intracellular delivery processes of viruses. Unlike conventional PEI-mediated transfection, molecular interaction-dependent gene delivery of VMPs was unaffected by the presence of serum and achieved higher efficiency without toxicity. By targeting overexpressed ICAM-1, VMPs delivered genes specifically to inflamed endothelial cells and macrophages both in vitro and in vivo. Simplicity and versatility of the platform and inflammation-specific delivery may open up opportunities for multifaceted gene therapy that can be translated into the clinic and treat a broad range of debilitating immune and inflammatory diseases.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kang
authors.forename: K
authors.initials: K
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Leelawattanachai
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.forename: T
authors.initials: T
authors.lastname: Park
authors.forename: I M
authors.initials: IM
authors.lastname: Min
authors.forename: M M
authors.initials: MM
authors.lastname: Jin
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007154:Immune System Diseases / Q000628:therapy; D007249:Inflammation / Q000628:therapy; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011094:Polyethyleneimine / Q000737:chemistry / Q000493:pharmacokinetics; D014771:Virion / Q000737:chemistry / Q000235:genetics
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D011094:Polyethyleneimine