Chenglong Li,Shuhao Xu,Xin Li,Huaiyu Su,Can Qian,Yingying Hou,Sanjun Shi
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation, damage, and disability. Activated fibroblast-like synoviocytes (FLSs), abundant in RA synovium, crucially facilitate disease progression. These activated FLSs drive RA pathogenesis by upregulating adhesion molecules, proinflammatory cytokines, chemokines, and major histocompatibility complex class II (MHC-II). This upregulation facilitates their interaction with CD4 + T cells, triggering an inflammatory cascade that exacerbates synovial inflammation. To address this, a DSPE-mPEG 2000 -GPA-KLVFF-decorated liposome loaded with dexamethasone (DPGK@Lipo-Dex) is developed to precisely target FLSs in arthritic joints. DPGK@Lipo-Dex achieves efficient binding to FLSs through a specific enzymatic interaction between fibroblast activation protein-α (FAP-α) and GPA, along with prolonged retention in the joints due to the fibrillar transformation of KLVFF. In vitro studies demonstrate that DPGK@Lipo-Dex enhances cellular uptake and reduces MHC-II expression on aggressive FLSs. In adjuvant-induced arthritis (AIA) rats, DPGK@Lipo shows specific distribution patterns that target both inflamed joints and FLSs. Treatment with DPGK@Lipo-Dex leads to a downregulation of MHC-II expression, a decrease in the number of activated T cells within the synovium, and a reduction in levels of proinflammatory mediators. Overall, DPGK@Lipo-Dex effectively suppresses FLSs-related responses and ultimately results in inflammatory remission. This makes DPGK@Lipo-Dex a promising candidate for nano-therapeutic treatment in rheumatoid arthritis.
The anticancer performance of nanomedicine is largely impeded by insufficient intratumoral penetration. Herein, tumor microenvironment (TME)-amendatory and self-adaptive nanoclusters (NCs) capable of cancer-associated fibroblasts (CAFs) depletion and size/charge conversion were engineered to mediate light-assisted, hierarchical intratumoral penetration. Particularly, large-sized NCs (~50 nm) were prepared via self-assembly of FAP-α-targeting peptide-modified, 1 O 2 -sensitive polymers, which were further used to envelope small-sized dendrimer (~5 nm) conjugated with Ce6 and loaded with DOX (DC/D). After systemic administration, the NCs efficiently targeted CAFs and generated lethal levels of 1 O 2 upon light irradiation, which depleted CAFs and concomitantly dissociated the NCs to liberate small-sized, positively charged DC/D. Such stroma attenuation and NCs transformation collectively facilitated the delivery of DC/D into deeper regions of CAF-rich tumors, where DOX and 1 O 2 provoked synergistic anti-cancer efficacies. This study provides an effective approach to facilitate the tumor penetration of nanomedicine by concurrently and spatiotemporally reconfiguring the nano-properties and remodeling the TME.
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