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.

Precise delivery of celastrol by PEGylated aptamer dendrimer nanoconjugates for enormous therapeutic effect via superior intratumor penetration over antibody counterparts.

Antibody-coated nanoparticles have been reported to have the extremely low delivery efficiency in solid tumors in preclinical trials. Though aptamers were considered to be superior over antibodies in cancer theranostics, whether PEGylated aptamer nanoparticles are better than antibody nanoparticles in improving delivery specificity and penetration efficiency of chemotherapeutics is still unknown. Here, we conjugate celastrol, a natural product with anti-tumor effect, onto PEGylated EpCAM aptamer or antibody dendrimers to obtain two nanoconjugates, and for the first time, conduct a comprehensive study to compare their performance in delivery specificity, intratumoral penetration ability and therapeutic outcomes. Our results showed that compared to antibody counterparts, PEGylated aptamer nanoconjugates exhibited the enhanced accumulation and retention specificities at tumor sites and the stronger intratumoral penetration capabilities by reducing the macrophage reservoir effects in solid tumors. When delivered celastrol to a colorectal xenograft tumor mice model by PEGylated aptamer dendrimers, 20 % of enhanced therapeutic efficiency was achieved compared to that by antibody-modified ones. Moreover, celastrol at 2 mg/kg delivered by PEGylated aptamer dendrimers showed the prominent anticancer efficiency (nearly 92 %) but without obvious side effects. These data firstly provide the proof-of-concept implementation that PEGylated aptamer nanoconjugates will display the great potential in the effective and safe cancer treatment with regard to the superiority over antibody ones in penetration abilities.

Hybrid Biomimetic Nanovesicles to Drive High Lung Biodistribution and Prevent Cytokine Storm for ARDS Treatment.

Acute respiratory distress syndrome (ARDS) has been a life threat for patients in ICUs. Vast efforts have been devoted, while no medication has proved viable, which may be ascribed to inadequate drug delivery to damaged tissues and insufficient control of lung inflammation. Given the anti-inflammatory role of M2-type macrophages, M2 macrophage-derived nanovesicles and lung-targeting liposomes are cofused to fabricate hybrid liposomes-nanovesicles (LNVs). Benefiting from the incorporated lung-homing moiety, LNVs demonstrate high pulmonary accumulation with a lung/liver ratio of 14.9, which is approximately 53.3-fold of free nanovesicles. Thus, M2 macrophage-derived nanovesicles can be delivered to lung tissues for executing immunoregulatory functions. LNVs display phagocytosis by the infiltrated neutrophils and macrophages, exhibiting sustained release of preloaded IKK-2 inhibitor (TPCA-1). The integrated nanosystems demonstrate multidimensional suppression of the overwhelming inflammation, such as decreasing infiltration of inflammatory cells, achieving restraint on cytokine storms and alleviating oxidative stress. Therefore, the improved therapeutic outcome in ARDS mice is obtained. Altogether, the hybrid nanoplatform provides a versatile drug delivery paradigm for integrating biological nanovesicles and therapeutic molecules by cofusion of nanovesicles with liposomes, improving lung biodistribution and accomplishing a boosted anti-inflammatory response for ARDS therapy.