C176-loaded and phosphatidylserine-modified nanoparticles treat retinal neovascularization by promoting M2 macrophage polarization

Retinal neovascularization(RNV),a typical pathological manifestation involved in most neovascular diseases,causes retinal detachment,vision loss,and ultimately irreversible blindness.Repeated intravitreal injections of anti-VEGF drugs were developed against RNV,with limitations of incomplete responses and adverse effects.Therefore,a new treatment with a better curative effect and more prolonged dosage is demanding.Here,we induced macrophage polarization to anti-inflammatory M2 phenotype by inhibiting cGAS-STING signaling with an antagonist C176,appreciating the role of cGAS-STING signaling in the retina in pro-inflammatory M1 polarization.C176-loaded and phosphatidylserine-modified dendritic mesoporous silica nanoparticles were constructed and examined by a single intravitreal injection.The biosafe nanoparticles were phagocytosed by retinal macrophages through a phosphatidylserine-mediated“eat me”signal,which persistently release C176 to suppress STING signaling and thereby promote macrophage M2 polarization specifically.A single dosage can effectively alleviate pathological angiogenesis phenotypes in murine oxygen-induced retinopathy models.In conclusion,these C176-loaded nanoparticles with enhanced cell uptake and long-lasting STING inhibition effects might serve as a promising way for treating RNV.

Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment

Rheumatoid arthritis(RA)is a common autoimmune disease leading to pain,disability,and even death.Although studies have revealed that aberrant activation of STING was implicated in various autoimmune diseases,the role of STING in RA remains unclear.In the current study,we demonstrated that STING activation was pivotal in RA pathogenesis.As the accumulation of dsDNA,a specific stimulus for STING,is a feature of RA,we developed a spherical polyethyleneimine-coated mesoporous polydopamine nanoparticles loaded with STING antagonist C-176(PEI-PDA@C-176 NPs)for treating RA.The fabricated NPs with biocompatibility had high DNA adsorption ability and could effectively inhibit the STING pathway and inflammation in macrophages.Intra-articular administration of PEI-PDA@C-176 NPs could effectively reduce joint damage in mice models of dsDNA-induced arthritis and collagen-induced arthritis by inhibiting STING pathway.We concluded that materials with synergistic effects of STING inhibition might be an efficacious strategy to treat RA.