Advancement in Inflammation-responsive Drug Delivery System for Chronic Inflammation.

Inflammation-Responsive Drug Delivery System (IR-DDS) is proposed as a novel strategy for targeted therapy of the chronic inflammation-associated diseases: inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and sepsis. These smart systems take advantage of the characteristic pathological microenvironment in inflamed tissues-such as acidic pH (5-6.5), high levels of reactive oxygen species (ROS), overexpressed enzymes, including matrix metalloproteinases (MMPs), and reductive conditions from glutathione (GSH)-for drug-specific accumulation at the site of action and on-demand release. By capitalizing on stimulus-induced behaviors, such as pH-activated protonation and swelling, ROS-stimulated bond scission in thio-ketals or boronic esters, enzyme-cleavable peptide linkers, or GSH-triggered disulfides, IR-DDS have overcome drawbacks of traditional delivery systems, including low bioavailability, off-target effects, and systemic toxicity. The review discusses a variety of carrier systems, such as polymeric nanoparticles (PLGA, chitosan), liposomes, micelles, hydrogels, dendrimers, and hybrid nanocomposites that offer inherent biocompatibility, controllable degradation, and multiple functionalities for sustained delivery. This includes the use of muscle, pH-sensitive hydrogels for periodontitis, oxidation-responsive polypropylene sulfide nanoparticles for anti-inflammatory drug release in rheumatoid arthritis models, and enzyme-triggered gelatin complexes used to target inflamed tissue in IBD, which are striking examples. A sulfasalazine-loaded transdermal patch is shown for chronic inflammation assessment, with increased efficacy in preclinical animal models, such as rat colitis and mouse arthritis after localized delivery. Despite encouraging preclinical findings in lowering cytokine levels, joint swelling, and inflammation markers, clinical translation is hindered by disease heterogeneity, scalability, biocompatibility issues, and manufacturing complexity. Future perspectives: AI-guided green multi-stimuli systems and therapeutic drug delivery, and diagnostic imaging (such as fluorescence, MRI) using multifunctional nanoparticle hybrids for personalized precision therapy will most likely revolutionize the management of chronic inflammation.