No abstract

No abstract

Wound care is a serious healthcare concern, often complicated by prolonged inflammation and bacterial infection, which contributes significantly to mortality and morbidity. Agents commonly used to treat chronic wound infections are limited due to toxicity of the therapy, multifactorial etiology of chronic wounds, deep skin infections, lack of sustained controlled delivery of drugs, and development of drug resistance. LL37 is an endogenous host defense peptide possessing antimicrobial activity and is involved in the modulation of wound healing. Serpin A1 (A1) is an elastase inhibitor and has been shown to demonstrate wound-healing properties. Hence, our goal was to develop a topical combination nanomedicine for the controlled sustained delivery of LL37 and A1 at precise synergistic ratio combinations that will significantly promote wound closure, reduce bacterial contamination, and enhance anti-inflammatory activity. We have successfully developed the first solid lipid nanoparticle (SLN) formulation that can simultaneously deliver LL37 and A1 at specific ratios resulting in accelerated wound healing by promoting wound closure in BJ fibroblast cells and keratinocytes as well as synergistically enhancing antibacterial activity against S. aureus and E. coli in comparison to LL37 or A1 alone.

RNA interference (RNAi)-mediated gene silencing offers a novel treatment and prevention strategy for human immunodeficiency virus (HIV) infection. HIV was found to infect and replicate in human brain cells and can cause neuroinfections and neurological deterioration. We designed dual-antibody-modified chitosan/small interfering RNA (siRNA) nanoparticles to deliver siRNA across the blood-brain barrier (BBB) targeting HIV-infected brain astrocytes as a strategy for inhibiting HIV replication. We hypothesized that transferrin antibody and bradykinin B2 antibody could specifically bind to the transferrin receptor (TfR) and bradykinin B2 receptor (B2R), respectively, and deliver siRNA across the BBB into astrocytes as potential targeting ligands. In this study, chitosan nanoparticles (CS-NPs) were prepared by a complex coacervation method in the presence of siRNA, and antibody was chemically conjugated to the nanoparticles. The antibody-modified chitosan nanoparticles (Ab-CS-NPs) were spherical in shape, with an average particle size of 235.7 ± 10.2 nm and a zeta potential of 22.88 ± 1.78 mV. The therapeutic potential of the nanoparticles was evaluated based on their cellular uptake and gene silencing efficiency. Cellular accumulation and gene silencing efficiency of Ab-CS-NPs in astrocytes were significantly improved compared to non-modified CS-NPs and single-antibody-modified CS-NPs. These results suggest that the combination of anti-Tf antibody and anti-B2 antibody significantly increased the knockdown effect of siRNA-loaded nanoparticles. Thus, antibody-mediated dual-targeting nanoparticles are an efficient and promising delivery strategy for inhibiting HIV replication in astrocytes. Graphical abstract Graphic representation of dual-antibody-conjugated chitosan nanoparticles for the targeted delivery of siRNA across the blood-brain barrier (BBB) for inhibiting HIV replication in astrocytes. a Nanoparticle delivery to the BBB and penetration. b TfR-mediated transcytosis of nanoparticles across the epithelial cells. c B2R-mediated endocytosis of nanoparticles in astrocytes. d The molecular interactions between HIV-1 Tat protein and Cyclin T1 and Tip110 cellular proteins. e A schematic representation of chitosan nanoparticles with its components. RNAPII RNA polymerase II, TAR transactivation response RNA element, LTR long terminal repeat, Ab antibody, CS chitosan, TPP tripolyphosphate.