A Dual-Targeted Metal–Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche

Abstract

Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of VSIg4 + lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bonetargeted delivery of the complement inhibitor CRIg−CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg−CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg−CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclastmediated bone resorption, and CRIg−CD59 can promote the repair of the VSIg4 + lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.

Immune checkpoints in rheumatoid arthritis: progress and promise

“…VSIG4 (complement receptor immunoglobulin; CRIg) is a B7family related protein capable of modulating T cells through interaction with a yet to be identified receptor and has additional roles in immunosuppression (110,111). VSIG4 binds the complement fragment C3b, inhibiting the alternative complement pathway (112), and approaches utilising this function have shown efficacy in rodent models of RA (113,114). Administration of soluble VSIG4 reduced disease severity and prevented bone erosion in murine arthritis models (114), and administration of the dual complement inhibitor CRIg-CD59 alleviated symptoms in an adjuvant-induced arthritis rat model (113).…”

“…VSIG4 binds the complement fragment C3b, inhibiting the alternative complement pathway (112), and approaches utilising this function have shown efficacy in rodent models of RA (113,114). Administration of soluble VSIG4 reduced disease severity and prevented bone erosion in murine arthritis models (114), and administration of the dual complement inhibitor CRIg-CD59 alleviated symptoms in an adjuvant-induced arthritis rat model (113). In humans, VSIG4 is expressed by tissue-resident regulatory macrophages in the healthy and RA ST from patients in remission (115), and importantly, polymorphisms in VSIG4 have been associated with RA severity (116).…”