Alternative splicing events as peripheral biomarkers for motor learning deficit caused by adverse prenatal environments.

Severity of neurobehavioral deficits in children born from adverse pregnancies, such as maternal alcohol consumption and diabetes, does not always correlate with the adversity's duration and intensity. Therefore, biological signatures for accurate prediction of the severity of neurobehavioral deficits, and robust tools for reliable identification of such biomarkers, have an urgent clinical need. Here, we demonstrate that significant changes in the alternative splicing (AS) pattern of offspring lymphocyte RNA can function as accurate peripheral biomarkers for motor learning deficits in mouse models of prenatal alcohol exposure (PAE) and offspring of mother with diabetes (OMD). An aptly trained deep-learning model identified 29 AS events common to PAE and OMD as superior predictors of motor learning deficits than AS events specific to PAE or OMD. Shapley-value analysis, a game-theory algorithm, deciphered the trained deep-learning model's learnt associations between its input, AS events, and output, motor learning performance. Shapley values of the deep-learning model's input identified the relative contribution of the 29 common AS events to the motor learning deficit. Gene ontology and predictive structure-function analyses, using Alphafold2 algorithm, supported existing evidence on the critical roles of these molecules in early brain development and function. The direction of most AS events was opposite in PAE and OMD, potentially from differential expression of RNA binding proteins in PAE and OMD. Altogether, this study posits that AS of lymphocyte RNA is a rich resource, and deep-learning is an effective tool, for discovery of peripheral biomarkers of neurobehavioral deficits in children of diverse adverse pregnancies.

Antibacterial, Adhesive, and Conductive Hydrogel for Diabetic Wound Healing.

Diabetic mellitus is one of the leading causes of chronic wounds and remains a challenging issue to be resolved. Herein, a hydrogel with conformal tissue adhesivity, skin-like conductivity, robust mechanical characteristics, as well as active antibacterial function is developed. In this hydrogel, silver nanoparticles decorated polypyrrole nanotubes (AgPPy) and cobalt ions (Co2+ ) are introduced into an in situ polymerized poly(acrylic acid) (PAA) and branched poly(ethylenimine) (PEI) network (PPCA hydrogel). The PPCA hydrogel provides active antibacterial function through synergic effects from protonated PEI and AgPPy nanotubes, with a tissue-like mechanical property (≈16.8 ± 4.5 kPa) and skin-like electrical conductivity (≈0.048 S m-1 ). The tensile and shear adhesive strength (≈15.88 and ≈12.76 kPa, respectively) of the PPCA hydrogel is about two- to threefold better than that of fibrin glue. In vitro studies show the PPCA hydrogel is highly effective against both gram-positive and gram-negative bacteria. In vivo results demonstrate that the PPCA hydrogel promotes diabetic wounds with accelerated healing, with notable inflammatory reduction and prominent angiogenesis regeneration. These results suggest the PPCA hydrogel provide a promising approach to promote diabetic wound healing.

Inflammation-responsive nanoparticles suppress lymphatic clearance for prolonged arthritis therapy.

The clearance of nanomedicine in inflamed joints has been accelerated due to the increased lymph angiogenesis and lymph flow in arthritic sites. To maximize the therapeutic efficacy for rheumatoid arthritis (RA), it is necessary to facilitate targeted delivery and extended drug retention in inflamed synovium simultaneously. In general, nanosized particles are more likely to achieve prolonged circulation and targeted delivery. While drug carriers with larger dimension might be more beneficial for extending drug retention. To balance the conflicting requirements, an inflammation-responsive shape transformable nanoparticle, comprised of amyloid ß-derived KLVFF peptide and polysialic acid (PSA), coupled with therapeutic agent dexamethasone (Dex) via an acid-sensitive linker, was fabricated and termed as Dex-KLVFF-PSA (DKPNPs). Under physiological condition, DKPNPs can keep stable nanosized morphology, and PSA shell could endow DKPNPs with long circulation and active targeting to arthritic sites. While in inflamed joints, acidic pH-triggered Dex dissociation or macrophages-induced specific binding with PSA would induce the re-assembly of DKPNPs from nanoparticles to nanofibers. Our results reveal that intravenously injected DKPNPs display prolonged in vivo circulation and preferential distribution in inflamed joints, where DKPNPs undergo shape transition to fibrous structures, leading to declined lymphatic clearance and prolonged efficacy. Overall, our dual-stimulus responsive transformable nanoparticle offers an intelligent solution to achieve enhanced therapeutic efficacy in RA.

Inflammation-homing "living drug depot" for efficient arthritis treatment.

Delivering therapeutic agents efficiently to inflamed joints remains an intractable problem in rheumatoid arthritis (RA) treatment due to the complicated physiological barriers. Circulating monocytes could selectively migrate to inflamed sites and differentiate into resident macrophages to aggravate RA. Therefore, a drug carrier that can be specifically internalized by circulating monocytes and switch monocytes into anti-inflammatory phenotype when reaching inflamed sites, might bypass the in vivo physiological barriers and achieve efficient RA therapy. Herein, we design a dextran sulfate (DS) functionalized nanoparticle (ZDNP) to selectively deliver anti-inflammatory agent dexamethasone (Dex) to circulating monocytes via the scavenger receptors on monocytes. Monocytes engulfing drug-loaded ZDNP could subsequently home to arthritic joints and act as a "living drug depot" to combat RA. Results revealed that ZDNP could be preferentially internalized by circulating monocytes when intravenously administrated in vivo. In a rat arthritic model, we found that circulating monocytes remarkably facilitated drug distribution and retention in inflamed joints. Moreover, monocytes engulfing drug-loaded nanoparticles exhibited favorable anti-inflammatory ability and M2-biased differentiation. Our work offers a facile approach to achieve site-directed anti-inflammatory therapy by taking advantage of the inflammation-homing ability of circulating monocytes. STATEMENT OF SIGNIFICANCE: Circulating monocytes can migrate to inflamed sites and then differentiate into macrophages to aggravate arthritis. Therefore, a drug carrier that can be specifically internalized by circulating monocytes and switch monocytes into anti-inflammatory phenotype when reaching inflamed sites may achieve efficient arthritis therapy. Here, we designed a monocyte-targeting nanoparticle (ZDNP) to selectively deliver anti-inflammatory Dex to circulating monocytes. When injected intravenously, ZDNP was effectively internalized by circulating monocytes via a scavenger receptor and subsequently was transported to arthritic joints, where monocytes engulfing the drug-loaded nanoparticles could switch to an anti-inflammatory phenotype to inhibit arthritis progress. We provide detailed evidence about the in vivo fate of ZDNP and unravel how monocytes act as a "living drug depot" to achieve site-directed arthritis therapy.