Ischemic stroke, a catastrophic neurological dysfunction attributable to cerebral blood stream interruption, stays the second main reason for mortality globally and a major contributor to long-term incapacity [1], [2], [3]. Reperfusion therapies, similar to thrombolysis and mechanical thrombectomy, are the usual medical interventions geared toward restoring blood stream [4]. Nevertheless, over 60 % of survivors nonetheless expertise persistent neurological deficits, largely because of secondary accidents induced by ischemia-reperfusion (I/R) [5]. Paradoxically, the fast restoration of oxygen throughout reperfusion results in the overproduction of reactive oxygen species (ROS), together with superoxide anions (•O2–), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH). This exacerbates oxidative stress and neuroinflammation [6], [7], finally inflicting irreversible neuronal harm. Due to this fact, assuaging ROS-mediated secondary harm has grow to be a pivotal therapeutic goal for enhancing useful restoration in ischemic stroke.
Regardless of promising preclinical outcomes with neuroprotective brokers in animal fashions [8], [9], their medical translation has largely failed. A significant hurdle is the restricted potential of those brokers to successfully cross the blood-brain barrier (BBB), particularly for macromolecular medication designed to exert anti-inflammatory and antioxidant results. Small-molecule medication additionally encounter challenges, similar to brief half-lives and fast systemic clearance, which considerably cut back their therapeutic efficacy [10]. Furthermore, many neuroprotectants show insufficient ROS-scavenging capability, fail to modulate the inflammatory microenvironment, and lack focused supply to ischemic areas [11]. Due to this fact, an optimum therapeutic technique ought to combine multifunctional capabilities, together with potent antioxidant/anti-inflammatory exercise, enhanced BBB permeability, minimized off-target results, and exact lesion concentrating on.
Biomedical nanotechnology supplies transformative options to those challenges. Engineered nanoparticles (NPs) can optimize drug pharmacokinetics, lengthen circulation time, decrease off-target toxicity, and allow exact site-specific supply [12], [13]. Amongst these, metal-polyphenol coordination complexes have emerged as a extremely versatile nanoplatform [14], [15], [16], [17]. These composites not solely mimic pure enzymatic actions (e.g., superoxide dismutase and catalase) for scavenging a number of ROS but in addition stabilize therapeutic cargo successfully [18]. Regardless of their promising purposes, standard metal-polyphenol nanoparticles have predominantly targeted on ROS neutralization, with restricted exploration of their potential to actively modulate the post-stroke inflammatory microenvironment or facilitate neuroregeneration. Moreover, present methods are sometimes hindered by low concentrating on effectivity and suboptimal security profiles throughout systemic circulation. Most approaches for crossing the BBB rely closely on passive diffusion by the disrupted BBB following ischemic occasions, failing to deal with the important requirement for energetic mechanisms that improve supply throughout later phases of restoration. The combination of multifunctional components-such as ROS scavenging, irritation modulation, BBB crossing, and neurorepair-into a unified nanoplatform stays an unmet medical want.
On this research, we developed a cerium-curcumin (Ce-Cur) hybrid nanoparticle to deal with the aforementioned gaps (Fig. 1). Curcumin, a pure polyphenol characterised by its β-diketone construction [19], not solely reveals potent anti-inflammatory, antioxidant, and neuroprotective results but in addition serves as an efficient chelating agent for steel ions. Cerium-based NPs, pushed by their redox-active Ce3+/Ce4+ biking, possess exceptional capabilities in scavenging ROS [20], making them extremely promising candidates for treating stroke and neurodegenerative illnesses. By coordinating curcumin with cerium ions, we efficiently synthesized Ce-Cur NPs that synergistically improve their antioxidant and anti inflammatory properties. To enhance lesion concentrating on, the NPs had been additional functionalized with macrophage-derived membranes, which exploit their inherent homing potential to inflammatory websites [21]. Furthermore, transferrin receptor (TfR)-activated peptides [22] had been included to allow energetic traversal of the BBB by receptor-mediated transcytosis, thereby overcoming the restrictions of passive diffusion. This dual-modification technique goals to realize exact supply to ischemic areas, successfully suppress ROS-driven harm, modulate neuroinflammation, and finally promote neural restore. This work establishes a multifunctional nanotherapeutic platform that bridges the hole between ROS scavenging and neurorestoration, offering a promising technique to boost outcomes in ischemic stroke and associated neurological problems.
