Author:
Suwan Keittisak,Yata Teerapong,Waramit Sajee,Przystal Justyna M.,Stoneham Charlotte A.,Bentayebi Kaoutar,Asavarut Paladd,Chongchai Aitthiphon,Pothachareon Peraphan,Lee Koon-Yang,Topanurak Supachai,Smith Tracey L.,Gelovani Juri G.,Sidman Richard L.,Pasqualini Renata,Arap Wadih,Hajitou Amin
Abstract
Bacteriophage (phage) have attractive advantages as delivery systems compared with mammalian viruses, but have been considered poor vectors because they lack evolved strategies to confront and overcome mammalian cell barriers to infective agents. We reasoned that improved efficacy of delivery might be achieved through structural modification of the viral capsid to avoid pre- and postinternalization barriers to mammalian cell transduction. We generated multifunctional hybrid adeno-associated virus/phage (AAVP) particles to enable simultaneous display of targeting ligands on the phage’s minor pIII proteins and also degradation-resistance motifs on the very numerous pVIII coat proteins. This genetic strategy of directed evolution bestows a next-generation of AAVP particles that feature resistance to fibrinogen adsorption or neutralizing antibodies and ability to escape endolysosomal degradation. This results in superior gene transfer efficacy in vitro and also in preclinical mouse models of rodent and human solid tumors. Thus, the unique functions of our next-generation AAVP particles enable improved targeted gene delivery to tumor cells.
Publisher
Proceedings of the National Academy of Sciences
Cited by
32 articles.
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