Nanoengineering of cyclic dinucleotide‑manganese complexes using biodegradable mesoporous silica nanoparticles for...

Cyclic dinucleotides (CDNs) are promising molecular adjuvants targeting stimulator of interferon genes (STING); however, their application has remained limited due to poor in vivo performance. Metal coordination polymer nanoparticles (MCP NPs) formulation with STING-stimulating metal ions can enhance the in vivo pharmacological properties and synergistically amplify STING activation of CDNs. Nevertheless, the controlled fabrication of robust MCP NPs remains challenging. Here, we report a facile nanoengineering of cyclic diadenosine monophosphate (CDA)‑manganese (Mn) coordination complex using a biodegradable mesoporous silica nanoparticle (bMSN) framework. bMSNs efficiently incorporated the nanoscale CDA-Mn complex through simple mixing and reaction, yielding stable CDA-Mn@bMSNs with physicochemical properties programmed by tailor-made bMSNs. CDA-Mn@bMSNs markedly enhanced STING signaling and subsequent activation of dendritic cells, accompanied by improved cellular uptake and cytosolic delivery. Additionally, CDA-Mn@bMSNs generated reactive oxygen species and killed cancer cells by inducing immunogenic cell death and apoptosis. In vivo studies demonstrated potent therapeutic efficacy of CDA-Mn@bMSNs against large established orthotopic melanoma in mice. Local and systemic immune analyses revealed the orchestration of antitumor immunity that supported strong therapeutic outcomes. Moreover, the combination with immune checkpoint blockade therapy further highlighted its potential to improve clinical cancer immunotherapy against highly aggressive and advanced metastatic melanoma. Overall, this study presents a promising engineering strategy for CDN-based MCP NPs to enhance the formulation and performance of STING-targeted cancer metallo-immunotherapy.