Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri-cross-linked inflammatory microenvironment-responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment-responsive hydrogel (OD-PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano-fillers into the hydrogel results in extra cross-linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple-network is achieved. The hydrogel has injectable, self-healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli-responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH-regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF-κB and MAPK pathways, exerting anti-inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple-network structure provides an effective strategy to treat IDs, holding great promise in clinical application.

Triple Cross-linked Dynamic Responsive Hydrogel Loaded with Selenium Nanoparticles for Modulating the Inflammatory Microenvironment via PI3K/Akt/NF-κB and MAPK Signaling Pathways.

Inflammatory dysregulation is intimately associated with the occurrence and progression of many life-threatening diseases. Accurate detection and timely therapeutic intervention on inflammatory dysregulation are crucial for the effective therapy of inflammation-associated diseases. However, the clinical outcomes of inflammation-involved disorders are still unsatisfactory. Therefore, there is an urgent need to develop innovative anti-inflammatory strategies by integrating emerging technological innovations with traditional therapeutics. Biomedical nanotechnology is one of the promising fields that can potentially transform the diagnosis and treatment of inflammation. In this review, we outline recent advances in biomedical nanotechnology for the diagnosis and treatment of inflammation, with special attention paid to nanosensors and nanoprobes for precise diagnosis of inflammation-related diseases, emerging anti-inflammatory nanotherapeutics, as well as nanotheranostics and combined anti-inflammatory applications. Moreover, the prospects and challenges for clinical translation of nanoprobes and anti-inflammatory nanomedicines are highlighted.

Nanotechnology in inflammation: cutting-edge advances in diagnostics, therapeutics and theranostics

A robust adaptive immune response is essential for combatting pathogens. In the wrong context such as due to genetic and environmental factors, however, the same mechanisms crucial for self-preservation can lead to a loss of self-tolerance. Resulting autoimmunity manifests in the development of a host of organ-specific or systemic autoimmune diseases, hallmarked by aberrant immune responses and tissue damage. The prevalence of autoimmune diseases is on the rise, medical management of which focuses primarily on pharmacological immunosuppression that places patients at a risk of side effects, including opportunistic infections and tumorigenesis. Biomaterial-based drug delivery systems confer many opportunities to address challenges associated with conventional disease management. Hydrogels, in particular, can protect encapsulated cargo (drug or cell therapeutics) from the host environment, afford their presentation in a controlled manner, and can be tailored to respond to disease conditions or support treatment via multiplexed functionality. Moreover, localized delivery to affected sites by these approaches has the potential to concentrate drug action at the site, reduce off-target exposure, and enhance patient compliance by reducing the need for frequent administration. Despite their many benefits for the management of autoimmune disease, such biomaterial-based approaches focus largely on the downstream effects of hypersensitivity mechanisms and have a limited capacity to eradicate the disease. In contrast, direct targeting of mechanisms of hypersensitivity reactions uniquely enables prophylaxis or the arrest of disease progression by mitigating the basis of autoimmunity. One promising approach is to induce self-antigen-specific tolerance, which specifically subdues damaging autoreactivity while otherwise retaining the normal immune responses. In this review, we will discuss hydrogel-based systems for the treatment of autoimmune disease, with a focus on those that target hypersensitivity mechanisms head-on. As the field continues to advance, it will expand the range of therapeutic choices for people coping with autoimmune diseases, providing fresh prospects for better clinical outcomes and improved quality of life. 

Hydrogel-based approaches to target hypersensitivity mechanisms underlying autoimmune disease

Purpose: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease involving synovial inflammation and joint destruction. Although therapeutic drugs for RA have some efficacy, they usually cause severe side effects and are expensive. RA is characterized by synovial hyperplasia, intra-articular hypoxia, upregulated expression of matrix metalloproteinases, and excessive accumulation of reactive oxygen species. The adverse microenvironment further aggravates activated macrophage infiltration. Therefore, controlling the microenvironment of diseased tissues and targeting the activated macrophages have become new therapeutic targets in RA patients. Methods: Here, microenvironment-targeting micelles (PVGLIG-MTX-Que-Ms) were synthesized using the thin film hydration method. In the inflammatory microenvironment, PVGLIG was cleaved by the highly expressed MMP-2, PEG 5000 was eliminated, MTX was exposed, macrophage activation was targeted, and Que enrichment was enhanced. The cytotoxicity, targeting, antioxidant, and anti-inflammatory properties of drug-loaded micelles were tested in vitro. The drug-loaded micelles were used to treat CIA rats. In vivo targeting, expression of serum inflammatory factors, immunohistochemistry of the articular cartilage, and changes in immuno-fluorescence staining were observed. Results: The developed micelles had a particle size of (89.62 ±1.33) nm and a zeta potential of (−4.9 ±0.53) mV. The IC 50 value of PVGLIG-MTX-Que-Ms (185.90 ±6.98) μmol/L was significantly lower than that of free Que (141.10 ±6.39) μmol/L. The synthesized micelles exhibited slow-release properties, low cytotoxicity, strong targeting abilities, and significant anti-inflammatory effects in vitro. In vivo, the drug-loaded micelles accumulated at the joint site for a long time. PVGLIG-MTX-Que-Ms significantly reduced joint swelling, improved bone destruction, and decreased the expression of serum inflammatory factors in CIA rats. Conclusion: The smart-targeting micelles PVGLIG-MTX-Que-Ms with strong targeting, anti-inflammatory, cartilage-protective, and other multiple positive effects are a promising new tool for RA treatment.

Microenvironmental Enzyme-Responsive Methotrexate Modified Quercetin Micelles for the Treatment of Rheumatoid Arthritis

ABSTRACT Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that often causes joint pain, swelling, and functional impairments. Drug therapy is the main strategy used to alleviate the symptoms of RA; however, drug therapy may have several adverse effects, such as nausea, vomiting, abdominal pain, diarrhea, gastric ulcers, intestinal bleeding, hypertension, hyperglycemia, infection, fatigue, and indigestion. Moreover, long‐term excessive use of drugs may cause liver and kidney dysfunction, as well as thrombocytopenia. Nanodrug delivery systems (NDDSs) can deliver therapeutics to diseased sites with the controlled release of the payload in an abnormal microenvironment, which helps to reduce the side effects of the therapeutics. Abnormalities in the microenvironment, such as a decreased pH, increased expression of matrix metalloproteinases (MMPs), and increased concentrations of reactive oxygen species (ROS), are associated with the progression of RA but also provide an opportunity to achieve microenvironment‐responsive therapeutic release at the RA site. Microenvironment‐responsive NDDSs may overcome the abovementioned disadvantages of RA therapy. Herein, we comprehensively review recent progress in the development of microenvironment‐responsive NDDSs for RA treatment, including pH‐, ROS‐, MMP‐, and multiresponsive NDDSs. Furthermore, the pathological microenvironment is highlighted in detail. 

Recent Progress in Microenvironment‐Responsive Nanodrug Delivery Systems for the Targeted Treatment of Rheumatoid Arthritis

Overexpressed matrix metalloproteinases, hypoxia microenvironment, and metabolic abnormality are important pathological signs of rheumatoid arthritis (RA). Designing a delivery carrier according to the pathological characteristics of RA that can control drug release in response to disease severity may be a promising treatment strategy. Psoralen is the main active ingredient isolated from Psoralea corylifolia L. and possesses excellent anti-inflammatory activities as well as improving bone homeostasis. However, the specific underlying mechanisms, particularly the possible relationships between the anti-RA effects of psoralen and related metabolic network, remain largely unexplored. Furthermore, psoralen shows systemic side effects and has unsatisfactory solubility. Therefore, it is desirable to develop a novel delivery system to maximize psoralen's therapeutic effect. In this study, a self-assembled degradable hydrogel platform is developed that delivers psoralen and calcium peroxide to arthritic joints and controls the release of psoralen and oxygen according to inflammatory stimulation, to regulate homeostasis and the metabolic disorder of the anoxic arthritic microenvironment. Therefore, the hydrogel drug delivery system based on the responsiveness of the inflammatory microenvironment and regulation of metabolism provides a new therapeutic strategy for RA treatment.

A Metabolic Driven Bio-Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis.

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A Metabolic Driven Bio-Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis.