In situ size amplification strategy reduces lymphatic clearance for enhanced arthritis therapy.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by painful swelling and inflammation, arising from the immune system attacking on healthy cells. However, arthritic sites often experience increased lymph flow, hastening drug clearance and potentially reducing treatment effectiveness. To address this challenge, an in situ size amplification has been proposed to reduce lymphatic clearance and thereby enhance arthritis therapy. This system has been developed based on a conjugate of dexamethasone (Dex) and polysialic acid (PSA), linked via an acid-sensitive linker, supplemented with bis-5-hydroxytryptamine (Bis-5HT) on the PSA backbone. Under physiological conditions, the system autonomously assembles into stable nanoparticles (PD5NPs), facilitating prolonged circulation and targeted delivery to inflamed joints. Upon arrival at arthritic joints, Bis-5HT reacts to elevated myeloperoxidase (MPO) levels and oxidative stress, prompting particle aggregation and in-situ size amplification. This in situ size amplification nanocarrier effectively reduces lymphatic clearance and serves as reservoirs for sustained Dex release in acidic pH environments within arthritic sites, thus continuously alleviating RA symptoms. Moreover, investigation on the underlying mechanism elucidates how the in situ size amplification nanocarrier influences the transportation of PD5NPs from inflamed joints to lymphatic vessels. Our study offers valuable insights for optimizing nanomedicine performance in vivo and augmenting therapeutic efficacy.