Biomimetic and microenvironment-adaptive nanoplatform potentiates photodynamic therapy of rheumatoid arthritis via H2S-Modulated oxygen metabolism.

Photodynamic therapy (PDT) enables the selective eradication of inflamed synovium to reverse joint destruction in rheumatoid arthritis (RA). Nonetheless, the synovial hypoxia and poor photosensitizer biodistribution in the arthritic joints profoundly restrain the clinical application of PDT. Herein, we constructed a multipronged nanosystem (MM@SC-HN) through hierarchical integration of macrophage membrane (MM) coating and hydrogen sulfide (H2S) donor (S-propargyl-cysteine, SPRC)/photosensitizer (Chlorine 6, Ce6) co-conjugated hyaluronic acid nanogels (SC-HN) for potentiated PDT of RA. Interestingly, MM@SC-HN demonstrated preferential accumulation in the inflamed joints rather than in the major organs due to the intrinsic inflammation chemotactic capacity of the MM cloak. Moreover, SPRC undergoes pH-triggered liberation in synovial fluid to generate therapeutic H2S, simultaneously alleviating hypoxia and amplifying Ce6-mediated PDT efficacy through mitochondrial respiration modulation. Consequently, MM@SC-HN profoundly reshaped the intricate joint microenvironment featured by inflammation, hypoxia, pannus formation, hyperplasia, and oxidative stress, which ultimately led to ameliorated paw swelling, diminished inflammation score, and enhanced joint repair in adjuvant-induced arthritis rats. In addition, MM@SC-HN exhibited desirable hemo/cyto/histological compatibility that favored clinical translation. Collectively, our study provides a smart nanoplatform for clinical RA treatment and represents a novel approach for reinforced PDT that is readily adaptable to various diseases.