Colon Targeting pH-Responsive Coacervate Microdroplets for Treatment of Ulcerative Colitis.

Ulcerative colitis (UC), an immune-mediated chronic inflammatory disease, drastically impacts patients' quality of life and increases their risk of colorectal cancer worldwide. However, effective oral targeted delivery and retention of drugs in colonic lesions are still great challenges in the treatment of UC. Coacervate microdroplets, formed by liquid-liquid phase separation, are recently explored in drug delivery as the simplicity in fabrication, spontaneous enrichment on small molecules and biological macromolecules, and high drug loading capacity. Herein, in this study, a biocompatible diethylaminoethyl-dextran hydrochloride/sodium polyphenylene sulfonate coacervates, coated with eudragit S100 to improve the stability and colon targeting ability, named EU-Coac, is developed. Emodin, an active ingredient in traditional Chinese herbs proven to alleviate UC symptoms, is loaded in EU-Coac (EMO@EU-Coac) showing good stability in gastric acid and pepsin and pH-responsive release behavior. After oral administration, EMO@EU-Coac can effectively target and retain in the colon, displaying good therapeutic effects on UC treatment through attenuating inflammation and oxidative stress response, repairing colonic epithelia, as well as regulating intestinal flora balance. In short, this study provides a novel and facile coacervate microdroplet delivery system for UC treatment.

Engineered Biomimetic Nanovesicles Based on Neutrophils for Hierarchical Targeting Therapy of Acute Respiratory Distress Syndrome.

Acute Respiratory Distress Syndrome (ARDS) is a clinically severe respiratory disease that causes severe medical and economic burden. To improve therapeutic efficacy, effectively targeting delivery to the inflamed lungs and inflamed cells remains an ongoing challenge. Herein, we designed engineered biomimetic nanovesicles (DHA@ANeu-DDAB) by fusion of lung-targeting functional lipid, neutrophil membrane containing activated ß2 integrins, and the therapeutic lipid, docosahexaenoic acid (DHA). By the advantage of lung targeting lipid and ß2 integrin targeting adhesion, DHA@ANeu-DDAB can first target lung tissue and further target inflammatory vascular endothelial cells, to achieve "tissue first, cell second" hierarchical delivery. In addition, the ß2 integrins in DHA@ANeu-DDAB could bind to the intercellular cell adhesion molecule-1/2 (ICAM-1/2) ligand on the endothelium in the inflamed blood vessels, thus inhibiting neutrophils' infiltration in the blood circulation. DHA administration to inflamed lungs could effectively regulate macrophage phenotype and promote its anti-inflammatory activity via enhanced biosynthesis of specialized pro-resolving mediators. In the lipopolysaccharide-induced ARDS mouse model, DHA@ANeu-DDAB afforded a comprehensive and efficient inhibition of lung inflammation and promoted acute lung damage repair. Through mimicking physiological processes, these engineered biomimetic vesicles as a delivery system possess good potential in targeting therapy for ARDS.

Biofunctional coacervate-based artificial protocells with membrane-like and cytoplasm-like structures for the treatment of persistent hyperuricemia.

Coacervate droplets formed by liquid-liquid phase separation have attracted considerable attention due to their ability to enrich biomacromolecules while preserving their bioactivities. However, there are challenges to develop coacervate droplets as delivery vesicles for therapeutics resulting from the lack of physiological stability and inherent lack of membranes in coacervate droplets. Herein, polylysine-polynucleotide complex coacervate droplets with favorable physiological stability are formulated to efficiently and facilely concentrate small molecules, biomacromolecules and nanoparticles without organic solvents. To improve the biocompatibility, the PEGylated phospholipid membrane is further coated on the surface of the coacervate droplets to prepare coacervate-based artificial protocells (ArtPC) with membrane-like and cytoplasm-like structures. The ArtPC can confine the cyclic catalytic system of uricase and catalase inside to degrade uric acid and deplete the toxicity of H2O2. This biofunctional ArtPC effectively reduces blood uric acid levels and prevents renal injuries in mice with persistent hyperuricemia. The ArtPC-based therapy can bridge the disciplines of synthetic biology, pharmaceutics and therapeutics.

Boosting B Cell and Macrophage-Mediated Humoral Immunity with Fusion Nanovesicles for Triple-Negative Breast Cancer Combined Therapy.

Cell-derived nanovesicles are widely utilized as therapeutic agents for cancer therapy. Current research mostly focuses on their ability to activate antitumor cellular immunity. However, whether they can activate and participate in antitumor humoral immunity is rarely studied. Here, doxorubicin-loaded hybrid cell nanovesicles (DNVs) are designed for boosting antitumor humoral and cellular immunity. The hybrid cell nanovesicles are generated through fusion of nanovesicles derived from M1-type macrophages and 4T1 tumor cells. It is found that DNVs can accumulate at tumor tissues and draining lymph nodes effectively, which results in the activation of antitumor immune response and significant inhibition of tumor progression. During this process, dendritic cells are effectively activated, subsequently inducing cytotoxicity T lymphocytes-mediated cellular immunity. Furthermore, DNVs elicit the antitumor humoral immunity through boosting T follicular helper cells and germinal center B cells. By analyzing the mechanism behind humoral immunity activation, it is found that M1-type macrophages repolarized by DNVs play an important role. In general, besides antitumor cellular immunity, the proposed hybrid nanovesicles provide a promising strategy for enhancing antitumor humoral immunity by macrophages repolarization and germinal center B cells activation.

Yeast Microcapsule Mediated Natural Products Delivery for Treating Ulcerative Colitis through Anti-Inflammatory and Regulation of Macrophage Polarization.

The common and frequent disease, ulcerative colitis (UC), causes serious physical and mental distress to patients. M2 macrophages have proven to play a role in anti-inflammation, which is a new potential target for UC therapy. In this study, we designed a safe and macrophages-targeting oral drug delivery system. Natural products, berberine (BBR), and Epigallocatechin Gallate (EGCG) with anti-inflammatory activity were assembled and encapsulated into yeast microcapsule (YM), generating therapeutic system BBR/MPN@YM. BBR and EGCG exhibited synergistic effects against UC through the effect of antioxidation. Through the interaction between ß-1,3-d-glucan on the surface of YM and dectin-1 receptors on macrophages, BBR/MPN@YM could be effectively transported to inflammation parts and internalized into macrophages, avoiding gastric degradation. In the in vivo UC mouse model, BBR/MPN@YM could transform M1 macrophages into anti-inflammatory M2 macrophages, thus exerting specific anti-inflammatory effects. Therefore, this BBR/MPN@YM targeted oral drug delivery system provided a new macrophages-targeting strategy for the clinical treatment of UC.