## 1 Introduction  
In 2019, stroke was responsible for a high mortality rate of 11.6% and a disability rate of 5.7%, making it the second-leading cause of death and the third-leading cause of disability globally. Ischemic strokes account for 62.4% of all stroke cases [1]. Currently, the primary treatments for acute ischemic stroke are intravenous rtPA injection and thrombectomy [2, 3], which aim to reperfuse the occluded area and salvage the ischemic penumbra [4]. However, rtPA is associated with a risk of intracerebral hemorrhage and must be administered within a 4.5 h window [5], with delays reducing its efficacy [6]. Despite the potential for acute or chronic brain ischemia to induce neuroprotection and prevent long-term neuronal damage [7], all clinically validated neuroprotective drugs have failed to date [8]. This underscores the urgent need to develop effective treatments for brain ischemia.  
Recent studies have demonstrated that compounds extracted from natural plants effectively treat various neurological disorders [9]. Loganin, a natural compound sourced from traditional Chinese medicinal plants such as Loasaceae, Gentianaceae, Rubiaceae, Cornaceae, and Caprifoliaceae [10, 11, 12, 13, 14], exhibits potent neuroprotective effects in cardiovascular and cerebrovascular diseases, including Alzheimer's disease, Parkinson's disease, and ischemia-reperfusion injuries [15, 16, 17, 18]. [PERSON] et al. demonstrated that pre-treatment with loganin significantly improves cell viability, reduces LDH release and ROS production, and increases intracellular mitochondrial membrane potential (MMP) in SH-SYSY cells subjected to H\({}_{2}\)O\({}_{2}\)-induced oxidative stress. Mechanism studies displayed that loganin impacts the phosphorylation of JNK/p38 and ERK 1/2 and modulates the Bcl-2/Bax apoptosis signaling pathway [19], indicating its potential as a neuroprotective agent.  
The blood-brain-barrier (BBB) presents a significant challenge for drug delivery to the brain. To overcome this obstacle, specific brain-targeting ligands can bind to endogenous receptors within the brain, facilitating the transport of drugs across the BBB [20]. Integrin \(\alpha\
u\beta 3\) is a transmembrane glycoprotein composed of \(\alpha\) and \(\beta\) subunits, which connect intracellular cytoskeletal elements to extracellular matrix molecules [21]. This integrin is believed to play a role in maintaining vascular integrity and remodeling during brain ischemia. It was demonstrated that an increased level of \(\alpha\
u\beta 3\) appears in the ischemic brain region at 2 h after middle cerebral artery occlusion (MCAO) [22]. Integrin \(\alpha\
u\beta 3\) binds to the Arg-Gly-Asp (RGD) sequence of its natural ligands, such as vitronectin, fibrinogen, osteopontin, and bone sialoprotein [23]. Accordingly, RGD-containing peptide analogs or recombinant proteins have been designed to target \(\alpha\
u\beta 3\)[24; 25]. [PERSON] et al. designed RGD-containing extracellular vesicles (EV) by attaching an RGD-containing recombinant protein to the EV surface. The RGD-EV exhibited the potential to target ischemic brain lesions and suppress post-stroke inflammation [26]. Further study demonstrated that the brain targeting delivery of RGD-EV was due to the binding of RGD-containing peptide to integrin \(\alpha\
u\beta 3\)[27].  
Based on the above information, we designed an integrin \(\alpha\
u\beta 3\) mediated ischemic brain regions delivery agent LA-Arg-Gly-Asp-Val (LA-1) via conjugating RGD-containing peptide and loganin. This design is aimed to enhance brain accumulation and improve the neuroprotective efficacy of LA-1.