Structural and functional evolution of IL-1 targeting: From systemic neutralization to bioengineered nanotherapies

The Interleukin-1 (IL-1) superfamily mediates critical inflammatory responses. While monoclonal antibodies targeting IL-1α and IL-1β have transformed the management of autoinflammatory, rheumatologic, and cardiovascular disease, their efficacy is often limited by poor tissue penetration, compensatory cytokine networks, and systemic immunosuppression risks. This Review traces the structural and functional evolution of IL-1 therapeutics from early polyclonal detection to modern high-affinity systemic neutralization. We examine the biophysical barriers restricting conventional immunoglobulins within necrotic and fibrotic microenvironments and discuss the emerging paradigm of dual-blockade bispecifics and combinatorial immunotherapies. Finally, we highlight the transition toward a "Bioengineering Era." By leveraging the superior diffusion kinetics of single-domain antibodies-such as camelid nanobodies and shark-derived VNARs-and integrating them with stimuli-responsive hydrogels and theranostic nanocarriers, we outline a paradigm shift from broad systemic blockade to precision, tissue-specific immunomodulation.