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

作　　者：Peng Hua Ruifeng Liang Suleixin Yang Yanbei Tu Meiwan Chen 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao SAR,China

出　　处：《Bioactive Materials》2024年第6期83-95,共13页生物活性材料（英文）

基　　金：supported by the Science and Technology Development Fund,Macao SAR(File no.0124/2019/A3);the University of Macao(File no.MYRG2022-00203-ICMS,MYRG-GRG2023-00134-ICMS-UMDF).

摘　　要：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(^(TK)PF)was constructed to bind the plasmid encoding pro-apoptotic gene PUMA with HSA coating layer(^(TK)PF/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.

关 键 词：Rheumatoid arthritis PUMA CELASTROL ANTI-INFLAMMATION Fibroblast-like synoviocyte apoptosis 

分 类 号：R593.22[医药卫生—内科学]