Designing Fullerene-Based Nanomedicines for Treating Inflammatory Diseases: From Molecular Mechanism to Clinical...

Inflammatory disease progression is tightly governed by the dynamic accumulation and amplification of excess reactive oxygen species (ROS). In the early phase, acute ROS bursts activate proinflammatory responses, inducing cellular injury. During the amplification stage, ROS act as pivotal signaling hubs, triggering immune imbalance and exacerbating metabolic disorder. In advanced stages, persistent ROS accumulation disrupts vascular endothelial and epithelial barriers, leaking inflammatory mediators into the circulation and generating systemic inflammatory storms. This continuum from cellular injury to immune amplification and barrier collapse represents a unifying pathological axis of inflammatory diseases. Conventional anti-inflammatory and antioxidant agents are insufficient to intercept this cascade. Their limitations restrict ROS scavenging efficiency, transient activity, and single-target effects render them ineffective against the multistage feature of ROS-driven pathology. Because of their unique π-conjugated cage structures and extraordinary radical sponge capacity, fullerenes provide a multifunctional material platform for inflammation intervention. Through rational functionalization, fullerene derivatives acquire water solubility, tissue enrichment, and microenvironmental responsiveness, enabling broad-spectrum ROS scavenging, mitochondrial protection, immune reprogramming, and barrier repair. Based on the logic of the ROS cascade pathology, we established a three-stage fullerene inflammation intervention paradigm. In the acute inflammation stage, fullerenes rapidly neutralize ROS, inhibiting inflammation and repairing tissue injury. In the amplification stage, functionalized fullerenes modulate immune cell polarization and restore metabolic balance, demonstrating efficacy in models of autoimmune and metabolic dysregulation-related inflammatory diseases. In the barrier disruption stage, oral fullerene formulations repair intestinal barriers, reduce systemic inflammation, and block inflammatory escalation, achieving cross-organ protection in cardiovascular and neurodegenerative inflammatory diseases. This Account systematically summarizes the mechanisms and applications of fullerenes for treating inflammatory diseases, emphasizing their alignment with the ROS pathological cascade, which enables cross-stage and cross-system regulation of inflammation. We anticipate that these strategies encompassing tissue injury repair, immune-metabolic rebalancing, and barrier restoration will increase the understanding of fullerene bioactivity and accelerate their translation into next-generation programmable therapeutics for complex inflammatory disorders.