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Rheumatoid arthritis (RA) is characterized by synovial inflammation and joint destruction, and is associated with macrophage polarization and osteoclast activation. Current therapeutic approaches lack disease-specific targeting and have systemic side effects. Therefore, a non-vectorized fusaricin-arginine conjugated nanoenzyme (MANZ) was constructed. This nanoenzyme targets M1 macrophages through specific transporters and accumulates in inflamed joints. It functions by eliminating reactive oxygen species, re-polarizing macrophages, and inhibiting osteoclast differentiation, alleviating joint lesions in animal models without systemic toxicity.
Rheumatoid arthritis is a chronic autoimmune disease with core pathological features of synovial inflammation and progressive joint destruction. Its occurrence is closely related to abnormal macrophage polarization and excessive activation of osteoclasts. Current clinical treatments have insufficient disease-targeting capabilities and are prone to systemic side effects, thus urgently requiring the development of specific-targeting therapeutic strategies.
The MANZ nanoenzyme was constructed through the covalent binding of L-arginine and fusaricin via the Mannich reaction, and self-assembly was driven by non-covalent interactions. This resulted in a non-vectorized fusaricin-arginine conjugated nanoenzyme (MANZ). It can selectively target M1 macrophages through the uptake pathway mediated by cationic amino acid transporter 2 (CAT2), achieving preferential enrichment in inflamed joints. Its mechanism involves the elimination of reactive oxygen species, re-polarization of M1 macrophages, and inhibition of osteoclast differentiation, forming a multi-modal therapeutic effect.
Firstly, the L-arginine and fusaricin were coupled through the Mannich reaction, and then self-assembly was induced by non-covalent interactions to construct the non-vectorized nanoenzyme MANZ. The targeting mechanism of MANZ was clarified as selective uptake by M1 macrophages mediated by CAT2. Multi-dimensional action pathways (reactive oxygen species elimination, macrophage phenotype regulation, and inhibition of osteoclast differentiation) were designed. Using a collagen-induced arthritis (CIA) mouse model, the targeting distribution, pathological relief effect, and biological safety of MANZ in vivo were evaluated.
MANZ can achieve preferential accumulation in inflamed joints; in the CIA mouse model, it can significantly reduce joint swelling symptoms, alleviate synovitis, and inhibit bone erosion; no systemic toxic reactions were observed throughout the treatment process.
This study integrates natural polyphenols and cationic amino acids, and uses self-assembly technology to construct a targeted-specific nanoplatform, providing a new design concept for targeted therapy of autoimmune diseases; its core lies in using the specific interactions of biomolecules to achieve targeted delivery and multi-effect treatment combination, providing a reference for the application of nanoenzymes in inflammatory-related diseases.
Original source:
Authors: Jiachang Hong, Penghao Ji, Jinxi An, Junchao Huang, Ziheng Bu, Xudong Zhang, Wei Liu, Tingyu Wu, Sen Wang, Wei Zhu, Yuhui Li, Jixian Wan, Sudan Xu, Minfeng Huo, Peng Wu - Journal: Advanced Science - Publication Date: 2026-01-05 - DOI: 10.1002/advs.202521864
