Targeted treatment of gouty arthritis by biomineralized metallic nanozyme-mediated oxidative stress-mitigating nanotherapy.

Gouty arthritis is characterized by chronic deposition of monosodium urate (MSU) crystals in the joints and other tissues, resulting in the production of excess reactive oxygen species (ROS) and proinflammatory cytokines that intensify synovial inflammation. This condition is mainly associated with inflammatory M1 macrophage activation and oxidative stress production. Hence, gout symptoms can often be resolved by eliminating M1 macrophage activation and scavenging oxidative stress in the inflamed areas. Herein, we developed M1-macrophage-targeting biomineralized metallic nanozymes (FALNZs) that deplete oxidative stress and reduce the M1 macrophage levels to mitigate gouty arthritis. Intra-articular injection of the FALNZs targets inflammatory macrophages and suppresses ROS levels in joints with MSU-crystal-induced arthritis. In addition, the FALNZs alleviate joint swelling, inflammatory cytokine production, and pathological features of the joints. Overall, the proposed therapeutic approach is biocompatible and is an effective ROS scavenger for the treatment of gouty pathogenesis.

Biomineralized Nanoscavenger Abrogates Proinflammatory Macrophage Polarization and Induces Neutrophil Clearance through Reverse Migration during Gouty Arthritis.

The deposition of monosodium urate (MSU) crystals induces the overexpression of reactive oxygen species (ROS) and proinflammatory cytokines in residential macrophages, further promoting the infiltration of inflammatory leukocytes in the joints of gouty arthritis. Herein, a peroxidase-mimicking nanoscavenger was developed by forming manganese dioxide over albumin nanoparticles loaded with an anti-inflammatory drug, indomethacin (BIM), to block the secretion of ROS and COX2-induced proinflammatory cytokines in the MSU-induced gouty arthritis model. In the MSU-induced arthritis mouse model, the BIM nanoparticles alleviated joint swelling, which is attributed to the abrogation of ROS and inflammatory cytokine secretions from proinflammatory macrophages that induces neutrophil infiltration and fluid building up in the inflammation site. Further, the BIM nanoparticle treatment reduced the influx of macrophages and neutrophils in the injured region by blocking migration and inducing reverse migration in the zebrafish larva tail amputation model as well as in MSU-induced peritonitis and air pouch mouse models. Overall, the current strategy of employing biomineralized nanoscavengers for arthritis demonstrates clinical significance in dual blocking of peroxides and COX2 to prevent influx of inflammatory cells into the sites of inflammation.

Thermosusceptible Nitric-Oxide-Releasing Nitrogel for Strengthening Antitumor Immune Responses with Tumor Collagen Diminution and Deep Tissue Delivery during NIR Laser-Assisted Photoimmunotherapy.

Combined cancer immunotherapy has demonstrated promising potential with an amplified antitumor response and immunosuppressive tumor microenvironment (TME) modulation. However, one of the main issues that cause treatment failure is the poor diffusion and insufficient penetration of therapeutic and immunomodulatory agents in solid tumors. Herein, a cancer treatment approach that combines photothermal therapy (PTT) and nitric oxide (NO) gas therapy for tumor extracellular matrix (ECM) degradation, along with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor that reduces tryptophan catabolism to kynurenine, and DMXAA, a stimulator of interferon gene (STING) agonist that stimulates antigen cross-presentation, is proposed to overcome this issue. Upon NIR (808 nm) laser irradiation, NO-GEL achieved the desired thermal ablation by releasing sufficient tumor antigens through immunogenic cell death (ICD). NO delivery triggered local diffusion of excess NO gas for effectively degrading tumor collagen in the ECM, homogeneously delivered NLG919 throughout the tumor tissue, inhibited IDO expression that was upregulated by PTT, and reduced the immune suppressive activities. The sustained release of DMXAA prolonged dendritic cell maturation and CD8+ T cell activation against the tumor. In summary, NO-GEL therapeutics offer a significant tumor regression with PTT and STING agonist combination that stimulates a durable antitumor immune response. Additional unification of IDO inhibition during PTT supplements the immunotherapy by reducing the T cell apoptosis and immune suppressive cell infiltration to TME. NO-GEL with the STING agonist and IDO inhibitor is an effective therapeutic combination to counter possible limitations during solid tumor immunotherapy.

Metallic Nanoparticle-Mediated Immune Cell Regulation and Advanced Cancer Immunotherapy.

Cancer immunotherapy strategies leveraging the body's own immune system against cancer cells have gained significant attention due to their remarkable therapeutic efficacy. Several immune therapies have been approved for clinical use while expanding the modalities of cancer therapy. However, they are still not effective in a broad range of cancer patients because of the typical immunosuppressive microenvironment and limited antitumor immunity achieved with the current treatment. Novel approaches, such as nanoparticle-mediated cancer immunotherapies, are being developed to overcome these challenges. Various types of nanoparticles, including liposomal, polymeric, and metallic nanoparticles, are reported for the development of effective cancer therapeutics. Metallic nanoparticles (MNPs) are one of the promising candidates for anticancer therapy due to their unique theranostic properties and are thus explored as both imaging and therapeutic agents. In addition, MNPs offer a dense surface functionalization to target tumor tissue and deliver genetic, therapeutic, and immunomodulatory agents. Furthermore, MNPs interact with the tumor microenvironment (TME) and regulate the levels of tumor hypoxia, glutathione (GSH), and reactive oxygen species (ROS) for remodulation of TME for successful therapy. In this review, we discuss the role of nanoparticles in tumor microenvironment modulation and anticancer therapy. In particular, we evaluated the response of MNP-mediated immune cells, such as dendritic cells, macrophages, T cells and NK cells, against tumor cells and analyzed the role of MNP-based cancer therapies in regulating the immunosuppressive environment.