Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis

• Published in: Bioactive materials Vol. 36; pp. 83 - 95
• Main Authors: Hua, Peng, Liang, Ruifeng, Yang, Suleixin, Tu, Yanbei, Chen, Meiwan
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.06.2024; KeAi Publishing Communications Ltd; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Anti-inflammation; Apoptosis; Arthritis; Cartilage; Celastrol; Cell activation; Cell death; Disease; Drug delivery; Drugs; Effectiveness; Fibroblast-like synoviocyte apoptosis; Fibroblasts; Gene therapy; Homeostasis; Human serum albumin; Hyaluronic acid; Hyperplasia; Inflammation; Macrophages; Medical research; Microenvironments; Natural products; Needles; NF-κB protein; Polyethyleneimine; Proteins; PUMA; Rheumatoid arthritis; Serum albumin; Signal transduction; Skin; Synoviocytes; Transfection; Tumor necrosis factor-TNF; Vectors (Biology); United States > US; China; Fibroblast-like synoviocyte apoptosis; PUMA; Rheumatoid arthritis; Celastrol; Anti-inflammation
• ISSN: 2452-199X; 2097-1192; 2452-199X
• DOI: 10.1016/j.bioactmat.2024.02.030

Abnormal proliferation of aggressive fibroblast-like synoviocytes (FLS) and perpetuate synovial inflammation can inevitably accelerate the progression of rheumatoid arthritis (RA). Herein, a strategy of simultaneously promoting FLS apoptosis and inhibiting inflammation as mediated by macrophages is proposed to restore synovial homeostasis for effective RA therapy. A hyaluronic acid-based dissolvable microneedle (MN) is fabricated for transdermal delivery of dual human serum albumin (HSA)-contained biomimetic nanocomplexes to regulate RA FLS and macrophages. Upon skin insertion, dual nanocomplexes are released rapidly from the MN and accumulate in RA joint microenvironment through both passive and active targeting as mediated by HSA. Thioketal-crosslinked fluorinated polyethyleneimine 1.8 K (TKPF) was constructed to bind the plasmid encoding pro-apoptotic gene PUMA with HSA coating layer (TKPF/pPUMA@HSA, TPH). TPH nanocomplexes can upregulate PUMA through RA FLS transfection to trigger efficient apoptosis. Also, HSA nanocomplexes encapsulating the classic anti-inflammatory natural product celastrol (Cel@HSA, CH) can inhibit inflammation of macrophages through blocking NF-κB pathway activation. TPH/CH MN can deplete RA FLS and inhibit M1 macrophage activation, suppress synovial hyperplasia as well as reduce bone and cartilage erosion in a collagen-induced arthritis (CIA) mouse model, demonstrating a promising strategy for efficient RA treatment. [Display omitted] •A microneedle loaded with dual nanocomplexes was developed to realize both FLS apoptosis and inflammatory inhibition.•TKPF exhibited higher transfection efficiency of PUMA plasmid in RA FLS.•CH NCs with pH-responsive release property suppressed the LPS-stimulated inflammatory responses of RAW264.7 macrophages.•TPH/CH MN attenuated CIA symptoms, reduce inflammation infiltration, relieve cartilage damage, and bone erosion.