Receptor-Modular Nanocaptors for Programmable Cytokine Sequestration

Abstract Pathological cytokine networks underlie inflammatory injury and tumor-associated immunosuppression, yet most cytokine-targeted therapies rely on molecularly fixed, pathway-specific antagonists. We present a receptor-modular nanomaterial strategy for constructing modular cytokine nanocaptors (MCNs) whose sequestration profiles can be reconfigured by exchanging receptor modules. Cytokine receptor ectodomains are engineered as independently producible serum albumin fusion proteins and coassembled with poly(L-lactic acid) (PLLA) into compositionally defined nanoparticles. This architecture decouples cytokine-binding specificity from nanoparticle structure, enabling high-density codisplay of multiple receptor modules on single particles. Representative MCNs simultaneously sequester IL-6, TNF-α, and IFN-γ and suppress cytokine-driven inflammatory signaling more effectively than matched soluble receptor mixtures. By altering module composition while preserving the same assembly framework, MCNs can be redirected from sequestering pro-inflammatory cytokines in sepsis, acute lung injury, and fulminant hepatitis to depleting immunosuppressive mediators in tumors. These results establish receptor-modular nanocaptors as programmable materials for disease-tailored cytokine sequestration and immune-microenvironment reconfiguration.