Traumatic brain injury (TBI) is one of the most serious injuries to the central nervous system, and millions of people suffer TBI every year from accidents, sports, and military conflicts [1]. TBI may result in permanent motor, sensory, and autonomic dysfunction [2, 3]. Due to the limited self-repair capacity of the nerves and the complex pathological changes, there is no effective treatment strategy. Clinically available treatments, including high-dose glucocorticoid shock therapy, are mostly palliative and have little effect on recovery of sensory and motor function [4]. Reducing glial scar hyperplasia and maximizing neuronal axonal growth within ischemic regions remain major challenges in the treatment of TBI.
Cell therapies, particularly those utilizing mesenchymal stromal cells (MSCs), have shown significant promise in regenerative medicine for treating various diseases, including TBI [5]. Administration of MSCs through various routes including intraarterial, intravenous, and intracereb ral has demonstrated significant therapeutic potential in experimental models of TBI [6–8]. However, each route presents specific limitations. Intracranial injection is constrained by the small amount of MSCs that can be administered, posing a challenge for achieving effective concentrations at the injury site [9]. Intraarterial injection, while potentially delivering MSCs more directly to the brain, carries the risk of inducing brain ischemia [10]. Intravenous administration, though less invasive, leads to a widespread distribution of MSCs, resulting in suboptimal localization and retention in the targeted brain regions [7]. MSC-derived exosomes (Mexo), which serve as nanocarriers for proteins, RNA, and lipids, have been demonstrated to modulate immune responses, and reduce inflammation [9–11]. Neovascularization is critical for TBI repair, as it provides the oxygen and nutrients necessary for neurogenesis, especially given the cerebral vasculature damage following the injury [12]. Mexo have been proven to promote angiogenesis, thereby accelerating nerve repair and neurological functional recovery after brain injury by fostering the growth of neuronal dendrites and axons [13].
These delivery challenges of MSCs highlight the promise of Mexo as a therapeutic alternative for TBI. Exosomes, being smaller and more stable than whole cells, can potentially overcome these hurdles by facilitating targeted delivery and retention at lesion sites [16]. Nonetheless, the development of efficient delivery systems and strategies to enhance the retention and efficacy of Mexo in the injured brain tissue remains a critical area for further research. Addressing these issues could significantly advance the therapeutic application of Mexo in TBI and improve outcomes for patients suffering from this condition.
The blood-brain barrier (BBB) serves as a critical defense mechanism, restricting most therapeutic agents from entering the brain and thus maintaining brain homeostasis. However, this selective permeability poses a significant challenge for the treatment of brain diseases [14]. Notably, during TBI, the integrity of the BBB is compromised, creating a window of opportunity for therapeutic agents to reach the lesion sites [15, 16]. Bovine serum albumin-based nanocarriers (BSA NPs), with particle sizes less than 100 nm, have demonstrated the capability to penetrate the BBB effectively [17]. This property positions them as promising vehicles for enhancing drug delivery to the brain. Research has indicated that albumin-based drug delivery nanosystems can substantially improve the efficiency of drug entry and retention within brain tissues [18, 19]. Therefore, albumin-based nanoparticles are one of the best options for brain drug delivery. Alitretinoin, a derivative of all-trans retinoic acid (9-cis-retinoic acid), has demonstrated potential in neuroprotection and nerve regeneration in several studies [23]. Retinoic acid is known to protect against central nervous system damage by promoting neuronal survival and growth and reducing inflammatory responses. Similarly, alitretinoin may influence the repair process following nerve injury through its anti-inflammatory and immunomodulatory properties.
In this study, we encapsulated the small-molecule nerve repair drug Alitretinoin (Ali) within bovine serum albumin (BSA) nanoparticles to form Ali-NPs, which can penetrate the blood-brain barrier. Subsequently, these Ali-NPs were further encapsulated with mesenchymal stem cell-derived exosomes (Mexo) through a co-extrusion process, resulting in the formation of Ali-NPs@Mexo (Scheme 1A). This novel nanosystem is designed to reduce glial scar hyperplasia in the TBI area and promote the growth of neuronal axons, thereby facilitating nerve repair (Scheme 1B). Our results demonstrate that this dual-encapsulation strategy not only effectively delivers Alitretinoin to the targeted brain regions but also leverages the unique properties of exosomes to modulate the inflammatory response and reshape the microenvironment, achieved a synergistic neuroprotective effect, highlighting its potential in the treatment of TBI.