pH-responsive CuS/DSF/EL/PVP nanoplatform alleviates inflammatory bowel disease in mice via regulating gut immunity and microbiota.

The clinical treatment of inflammatory bowel disease (IBD) is challenging. We developed copper sulfate (CuS)/disulfiram (DSF)/methacrylic acid-ethyl acrylate copolymer (EL)/polyvinylpyrrolidone (PVP) nanoplatform (CuS/DSF/EL/PVP) and evaluated its efficiency for treating IBD. After oral administration, the pH-sensitive EL protected the CuS/DSF/EL/PVP against degradation by acidic gastric juices. Once the colon was reached, EL was dissolved, releasing DSF and Cu2+. Further, the main in vivo metabolite of DSF can bind to Cu2+ and form copper (II) N, N-diethyldithiocarbamate (CuET), which significantly alleviated acute colitis in mice. Notably, CuS/DSF/EL/PVP outperformed CuS/EL/PVP and DSF/EL/PVP nanoplatforms in reducing colonic pathology and improving the secretion of inflammation-related cytokines (such as IL-4 and IL-10) in the colonic mucosa. RNA-seq analysis revealed that the nanoplatform reduced colonic inflammation and promoted intestinal mucosal repair by upregulating C-type lectin receptor (CLR)-related genes and signaling pathways. Furthermore, CuS/DSF/EL/PVP showed potential for improving colitis Th1/Th17 cells through innate immunity stimulation, down-regulation of inflammatory cytokines, and upregulation of anti-inflammatory cytokines. Additionally, the intervention with CuS/DSF/EL/PVP led to increased intestinal flora diversity, decreased Escherichia-Shigella abundance, and elevated levels of short-chain fatty acid (SCFA)-producing bacteria Prevotella, Lactobacillus, and Bifidobacterium, indicating their potential to modulate the dysregulated intestinal flora and suppress inflammation. STATEMENT OF SIGNIFICANCE: Our study introduces the CuS/DSF/EL/PVP nanoplatform as a therapeutic strategy for treating inflammatory bowel disease (IBD). This approach demonstrates significant efficacy in targeting the colon and alleviating acute colitis in mice. It uniquely modulates gut immunity and microbiota, exhibiting a notable impact on inflammation-related cytokines and promoting intestinal mucosal repair. The nanoplatform's ability to regulate gut flora diversity, combined with its cost-effective and scalable production, positions it as a potentially transformative treatment for IBD, offering new avenues for personalized medical interventions.

Enhanced photothermal and chemotherapy of pancreatic tumors by degrading the extracellular matrix.

The degradation of extracellular matrix (ECM) to increase drug permeability is an attractive approach to enhancing pancreatic cancer therapy efficiency. Herein, polypyrrole nanoparticles (PPy NPs) were prepared by a template-guided chemical oxidation method. These PPy NPs with abundant surface pores were used to load the anticancer drug doxorubicin (DOX). In order to intelligently control the DOX release, PPy/DOX NPs were further entrapped with a thermoresponsive ligand, lauric acid (LA), to form PPy-LA/DOX NPs. Bromelain (BL) was then grafted onto the surface of PPy-LA NPs or PPy-LA/DOX NPs through an amidation reaction with the carboxyl group of LA. It was found that the DOX release of PPy-LA/DOX NPs was pH and temperature responsive, reaching a maximum amount of 85.9% within 48 h at pH = 5.4 and 50 °C. Moreover, it was demonstrated that the resultant PLB (PPy-LA-BL) NPs could efficiently hydrolyze the collagen in ECM and enhance the permeability of DOX to the pancreatic tumor. Remarkably, PLB NPs not only featured admirable photothermal conversion but also exhibited obvious photoacoustic imaging capability, which enabled imaging-guided enhanced tumor ablation. This study is anticipated to provide a feasible strategy to improve the permeability of nanoparticles to tumors.