Multimodal nanoimmunotherapy engages neutrophils to eliminate Staphylococcus aureus infections.

The increasing prevalence of antimicrobial resistance in Staphylococcus aureus necessitates alternative therapeutic approaches. Neutrophils play a crucial role in the fight against S. aureus but suffer from deficiencies in function leading to increased infection. Here we report a nanoparticle-mediated immunotherapy aimed at potentiating neutrophils to eliminate S. aureus. The nanoparticles consist of naftifine, haemoglobin (Hb) and a red blood cell membrane coating. Naftifine disrupts staphyloxanthin biosynthesis, Hb reduces bacterial hydrogen sulfide levels and the red blood cell membrane modifies bacterial lipid composition. Collectively, the nanoparticles can sensitize S. aureus to host oxidant killing. Furthermore, in the infectious microenvironment, Hb triggers lipid peroxidation in S. aureus, promoting neutrophil chemotaxis. Oxygen supplied by Hb can also significantly enhance the bactericidal capability of the recruited neutrophils by restoring neutrophil respiratory burst via hypoxia relief. This multimodal nanoimmunotherapy demonstrates excellent therapeutic efficacy in treating antimicrobial-resistant S. aureus persisters, biofilms and S. aureus-induced infection in mice.

Non-viral approaches for gene therapy and therapeutic genome editing across the blood-brain barrier.

The success of brain-targeted gene therapy and therapeutic genome editing hinges on the efficient delivery of biologics bypassing the blood-brain barrier (BBB), which presents a significant challenge in the development of treatments for central nervous system disorders. This is particularly the case for nucleic acids and genome editors that are naturally excluded by the BBB and have poor chemical stability in the bloodstream and poor cellular uptake capability, thereby requiring judiciously designed nanovectors administered systemically for intracellular delivery to brain cells such as neurons. To overcome this obstacle, various strategies for bypassing the BBB have been developed in recent years to deliver biologics to the brain via intravenous administration using non-viral vectors. This review summarizes various brain targeting strategies and recent representative reports on brain-targeted non-viral delivery systems that allow gene therapy and therapeutic genome editing via intravenous administration, and highlights ongoing challenges and future perspectives for systemic delivery of biologics to the brain via non-viral vectors.

Overcoming the Blood-Brain Barrier for Gene Therapy via Systemic Administration of GSH-Responsive Silica Nanocapsules.

CRISPR genome editing can potentially treat the root causes of many genetic diseases, including central nervous system (CNS) disorders. However, the promise of brain-targeted therapeutic genome editing relies on the efficient delivery of biologics bypassing the blood-brain barrier (BBB), which represents a major challenge in the development of CRISPR therapeutics. We created and screened a library of glutathione (GSH)-responsive silica nanocapsules (SNCs) for brain targeted delivery of biologics via systemic administration. In vivo studies demonstrate that systemically delivered SNCs conjugated with glucose and rabies virus glycoprotein peptide under glycemic control can efficiently bypass the intact BBB, enabling brain-wide delivery of various biologics including CRISPR genome editors targeting different genes in both Ai14 reporter mice and wild-type mice. In particular, up to 28% neuron editing via systemic delivery of Cre mRNA in Ai14 mice, up to 6.1% amyloid precursor protein (App) gene editing (resulting in 19.1% reduction in the expression level of intact APP), and up to 3.9% tyrosine hydroxylase (Th) gene editing (resulting in 30.3% reduction in the expression level of TH) in wild-type mice are observed. This versatile SNC nanoplatform may offer a novel strategy for the treatment of CNS disorders including Alzheimer's, Parkinson's, and Huntington's disease.