Electro-Magnetic Nano-Particle Bound Beclin1 siRNA Crosses the Blood-Brain Barrier to Attenuate the Inflammatory Effects of HIV-1 Infection in Vitro.
The purpose of this study was to evaluate a novel drug delivery system comprised of ferric-cobalt electro-magnetic nano-material (CoFe2O4@ BaTiO3; MENP) bound to siRNA targeting Beclin1 (MENP-siBeclin1) to cross the blood-brain barrier (BBB) and attenuate the neurotoxic effects of HIV-1 infection in the central nervous system following on-demand release of siRNA using an in vitro primary human BBB model. Beclin1 is a key protein in the regulation of the autophagy pathway and we have recently demonstrated the importance of Beclin1 in regulating viral replication and viral-induced inflammation in HIV-1-infected microglia. The MENP-siBeclin1 nano-formulation did not compromise the physiological function or integrity of the BBB model. Furthermore, the in vitro BBB data revealed that MENP-siBeclin1 could efficiently attenuate viral replication and viral-induced inflammation, likely due to STAT1/ NF-κB signaling pathways. MENP-siBeclin1 also silenced Beclin1 protein expression in HIV-1-infected microglial cells within the model system. In addition, the cytotoxic effects of direct treatment with siBeclin1 and MENP alone or in nano-formulation on primary human neuronal cells showed a minimal amount of cell death. Overall, the data shows that the nano-formulation can silence the BECN1 gene as an effective mechanism to attenuate HIV-1 replication and viral-induced inflammation in the context of the BBB.
Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA.
Myosotys
M
Rodriguez
Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA.
Ajeet
A
Kaushik
Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA.
Jessica
J
Lapierre
Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA.
Seth M
SM
Dever
Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA. nelhage@fiu.edu.
Nazira
N
El-Hage
Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA.
Madhavan
M
Nair
D000071186:Beclin-1 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002478:Cells, Cultured; D055590:Electromagnetic Phenomena; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D015497:HIV-1; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053768:Metal Nanoparticles / Q000008:administration & dosage; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
D000071186:Beclin-1; D034741:RNA, Small Interfering
Autophagy; Blood–brain barrier; HIV-1; Magneto-electric nano-particles; Neuro-inflammation; RNA interference