(T1430-07-41) MMP-Sensitive Nanomedicine for Macrophage-Targeted Delivery of Coenzyme Q10

Purpose: Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by chronic inflammation of the synovial joints and surrounding tissues. It primarily affects the synovium, a membrane lining the joints that plays a key role in maintaining joint function, driven by activated immune cells like macrophages and fibroblast-like synoviocytes (FLS). These cells contribute to synovial hyperplasia and secrete pro-inflammatory cytokines and matrix metalloproteinases (MMPs), leading to progressive joint damage. Targeted drug delivery to synovial macrophages presents a promising therapeutic approach to mitigate inflammation and tissue destruction. This study aims to develop a novel MMP-sensitive nanomedicine for selective delivery of coenzyme Q10 (CoQ10) to macrophages in inflamed synovial tissue. The nanomedicine, containing an MMP-sensitive polymer (PEG2k-pp-PE) and phosphatidylserine (PS), could respond to the MMP-2/9 overexpression in inflamed synovium, triggering PS-mediated phagocytosis for precise drug delivery (Figure 1).

Methods: MMP-sensitive PEG2k-pp-PE/PS nanoparticles were formulated using the thin film hydration technique to encapsulate hydrophobic CoQ10. The nanomedicine was characterized for key physicochemical properties, including particle size, zeta potential, drug loading efficiency, and in vitro drug release profile. The performance of the nanomedicine was evaluated using cell monocultures and co-cultures (macrophages and fibroblasts). The cellular uptake and cell selectivity were determined by fluorescence microscopy and flow cytometry. The effects of the nanomedicine on inflammatory cytokines and cell surface markers as well as macrophage activation were analyzed by ELISA, flow cytometry, and confocal microscopy.

Results: The hydrophobic CoQ10 was loaded into PEG2k-pp-PE/PS nanoparticles at a loading rate of about 9.5%. The nanoparticles had a mean particle size of < 200 nm with a uniform size distribution and a zeta potential of around -40 mV, ensuring their stable colloidal properties. The prepared nanoparticles showed MMP-dependent, macrophage-selective uptake indicating their sensitivity to the RA-associated inflammatory conditions with upregulated MMPs. The CoQ10-loaded nanomedicine significantly suppressed pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β, but enhanced anti-inflammatory cytokine IL-10 production. The macrophage activation markers CD80, CD86 and MHC class II were downregulated which indicated successful inflammation inhibition. The anti-inflammatory effects of the CoQ10-loaded nanomedicine were MMP-dependent.

Conclusion: The MMP-sensitive, macrophage-targeted CoQ10 nanomedicine showed strong anti-inflammatory effects and effective immunomodulation in vitro, which makes it a promising therapeutic strategy for RA. This dual-targeted system improves drug precision in suppressing pathological inflammation while decreasing drug doses and minimizing off-target side effects. These findings support further evaluation and development of this platform for inflammation/macrophage-specific drug delivery and treatment for RA and other inflammatory disorders.

Acknowledgements: There is no conflict of interest disclosed by all authors.


Figure 1. The MMP Sensitive macrophage Targeting Nano Particles (STNPs) composed of two components: PEG2k-pp-PE (MMP sensitive polymer) and PS (macrophage targeting ligand). The PS is exposed upon the MMP-induced PEG removal in the inflamed synovium (A). Then, macrophages recognize and engulf the nanoparticles via PS-mediated phagocytosis (B). The CoQ10-loaded STNPs showed MMP-dependent inflammation inhibition (C).