The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer’s, Parkinson’s and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a noninvasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPN in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60 nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain.

No abstract

with antimicrobial protein granules and enzymes. [5] NETs have been observed to be lethal to a number of bacteria, [6] fungi, [7] viruses, [8] and parasites, [9] yet some pathogenic bacteria can evade NET-induced killing. [10,11] Accumulation of excessive NETs in vivo is also associated with pathology of bacterial biofilm, autoimmune disease, and even cancer. [12] These complex and sometimes contradictory observations highlight the need to investigate NET-related physiological interactions with simpler but defined NET-like biomaterials. Isolation of NETs from neutrophils requires repeated centrifugation and washing steps, [13] which often causes unpredictable loss of proteins. Moreover, NETs can be triggered via chemical stimulus, [14] virulence factors, [15] and bacteria [16] under different pathways, yielding 33 common proteins and as much as 50 variable proteins. [12] While the existing antibodies and inhibitors are employed to block and characterize the function of specific NET components, their high complexity imposes limitations. [17] Here, we take a bottom-up approach of synthesizing NET-like materials with defined composition, termed "microwebs," through sonochemical complexation of lambda phage DNA and histone in aqueous solutions. Lambda phage DNA can spontaneously polymerize into networks in the presence of histone, [18] which facilitates formation of web-like structure. Escherichia coli UTI89 was used as a model pathogen Neutrophil extracellular traps (NETs) are decondensed chromatin networks released by neutrophils that can trap and kill pathogens but can also paradoxically promote biofilms. The mechanism of NET functions remains ambiguous, at least in part, due to their complex and variable compositions. To unravel the antimicrobial performance of NETs, a minimalistic NET-like synthetic structure, termed "microwebs," is produced by the sonochemical complexation of DNA and histone. The prepared microwebs have structural similarity to NETs at the nanometer to micrometer dimensions but with welldefined molecular compositions. Microwebs prepared with different DNA to histone ratios show that microwebs trap pathogenic Escherichia coli in a manner similar to NETs when the zeta potential of the microwebs is positive. The DNA nanofiber networks and the bactericidal histone constituting the microwebs inhibit the growth of E. coli. Moreover, microwebs work synergistically with colistin sulfate, a common and a last-resort antibiotic, by targeting the cell envelope of pathogenic bacteria. The synthesis of microwebs enables mechanistic studies not possible with NETs, and it opens new possibilities for constructing biomimetic bacterial microenvironments to better understand and predict physiological pathogen responses. Biomimetics Nature uses a variety of extracellular nanofibers, such as cobwebs, [1] amyloid plaques, [2] and fibrin clots [3] to capture invading microbes. As part of human innate immunity, neutrophils squirt decondensed chromatin networks to capture and disarm bacteria and fungi-a host defense pro...

Stimulator of interferon genes (STING) activation by intratumoral STING agonist treatment has been recently shown to eradicate tumors in preclinical models of cancer immunotherapy, generating intense research interest and leading to multiple clinical trials. However, there are many challenges associated with STING agonist‐based cancer immunotherapy, including low cellular uptake of STING agonists. Here, biodegradable mesoporous silica nanoparticles (bMSN) with an average size of 80 nm are developed for efficient cellular delivery of STING agonists. STING agonists delivered via bMSN potently activate innate and adaptive immune cells, leading to strong antitumor efficacy and prolonged animal survival in murine models of melanoma. Delivery of immunotherapeutic agents via biodegradable bMSN is a promising approach for improving cancer immunotherapy.

Extracellular traps (ETs), such as neutrophil extracellular traps, are a physical mesh deployed by immune cells to entrap and constrain pathogens. ETs are immunogenic structures composed of DNA, histones, and an array of variable protein and peptide components. While much attention has been paid to the multifaceted function of these structures, mechanistic studies of ETs remain challenging due to their heterogeneity and complexity. Here, we report a novel DNA-histone mesostructure (DHM) formed by complexation of DNA and histones into a fibrous mesh. DHMs mirror the DNA-histone structural frame of ETs and offer a facile platform for cell culture studies. We show that DHMs are potent activators of dendritic cells and identify both the methylation state of DHMs and physical interaction between dendritic cells and DHMs as key tuning switches for immune stimulation. Overall, our DHM platform provides a new opportunity to study the role of ETs in immune activation and pathophysiology. Main TextNucleic acids have long been established as immunostimulants, serving as both pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) released during infection and injury, respectively. [1] While previous studies have mainly focused on the immunogenicity of soluble nucleic acids from bacterial, viral, and endogenous sources, [2,3] recent findings have reported the potent immunostimulatory potential of nucleic acids electrostatically complexed to natural or synthetic polycations, including lipids, [4] peptides, [5] and proteins. [6] In a