Transdermal drug delivery patches based on hydrogels are widely used for the transdermal delivery of diverse drugs. However, most hydrogels do not exhibit adequate adhesiveness to skin surface. Herein, tissue adhesive hydrogels consisting of polyacrylamide/polydopamine (PAM/PDA) hydrogels embedded with extra-large pore mesoporous silica nanoparticles (XL-MSNs) are proposed based on the synergy of cohesive and adhesive properties. The incorporation of XL-MSNs leads to enhanced strength and adhesiveness to skin tissue due to an increased cohesive property derived from molecular interactions between XL-MSNs and polymer chains. The application of XL-MSNs to the hydrogel-skin tissue interface leads to a further enhanced adhesiveness due to the adhesive gluing role of XL-MSNs on the interface. The optimized condition enables a 4.9-fold increase in adhesion energy on the porcine skin tissue, compared to the control PAM/PDA patch. Strong adhesion is achieved immediately after the hydrogel patch is attached onto the skin as well as the surfaces of other organs. Finally, transdermal drug delivery through porcine skin is demonstrated by using the hydrogel patch, with a model drug loaded in the XL-MSNs embedded in the patch. These observations indicate a simple but highly effective strategy for preparing a highly adhesive hydrogel patch for transdermal drug delivery.

Owing to the limitations of conventional cancer therapies, cancer immunotherapy has emerged for the prevention of cancer recurrence. To provoke adaptive immune responses that are antigen-specific, it is important to develop an efficient antigen delivery system that can enhance the activation and maturation of the dendritic cells (DCs) in the human body. In this study, we synthesize hollow mesoporous silica nanoparticles with extra-large mesopores (H-XL-MSNs) based on a single-step synthesis from core–shell mesoporous silica nanoparticles with a core composed of an assembly of iron oxide nanoparticles. The hollow void inside the mesoporous silica nanoparticles with large mesopores allows a high loading efficiency of various model proteins of different sizes. The H-XL-MSNs are coated with a poly­(ethyleneimine) (PEI) solution to provide an immune adjuvant and change the surface charge of the particles for loading and slow release of a model antigen. An in vitro study using a cancer vaccine based on the PEI-coated H-XL-MSNs with the loading of the model antigen showed an enhanced activation of the DCs. An in vivo study demonstrated that the resulting cancer vaccine increased the antigen-specific cytotoxic T cells, enhanced the suppression of tumor growth, and improved the survival rate after challenging cancer to mice. These findings suggest that these hollow MSNs with extra-large pores can be used as excellent antigen carriers for immunotherapy.

In article number 2004407, Jaeyun Kim and co-workers describe a hydrogel patch with enhanced strength and high adhesiveness to skin tissue. The incorporation of mesoporous silica nanoparticles within the polydopamine-based hydrogel and between the hydrogel-tissue interface leads to significant enhancements of adhesiveness of the hydrogel to skin. The rapid adhesion and sustained drug delivery through the skin could allow for a hydrogel patch for transdermal drug delivery.

Sphingosine 1-phosphate (S1P) is a potent vasculoprotective and neuroprotective signaling lipid, synthesized primarily by sphingosine kinase 2 (SK2) in the brain. We have reported pronounced loss of S1P and SK2 activity early in Alzheimer's disease (AD) pathogenesis, and an inverse correlation between hippocampal S1P levels and age in females, leading us to speculate that loss of S1P is a sensitizing influence for AD. Paradoxically, SK2 was reported to mediate amyloid ␤ (A␤) formation from amyloid precursor protein (APP) in vitro. To determine whether loss of S1P sensitizes to A␤-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APP SwInd) mice. SK2 deficiency greatly reduced A␤ content in J20 mice, associated with significant improvements in epileptiform activity and cross-frequency coupling measured by hippocampal electroencephalography. However, several key measures of APP SwInd-dependent neurodegeneration were enhanced on the SK2-null background, despite reduced A␤ burden. These included hippocampal volume loss, oligodendrocyte attrition and myelin loss, and impaired performance in Y-maze and social novelty memory tests. Inhibition of the endosomal cholesterol exporter NPC1 greatly reduced sphingosine phosphorylation in glial cells, linking loss of SK2 activity and S1P in AD to perturbed endosomal lipid metabolism. Our findings establish SK2 as an important endogenous regulator of both APP processing to A␤, and oligodendrocyte survival, in vivo. These results urge greater consideration of the roles played by oligodendrocyte dysfunction and altered membrane lipid metabolic flux as drivers of neurodegeneration in AD.