Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases

Abstract

Neurodegenerative diseases (NDD) are characterized by the progressive loss of neurons and the impairment of cellular functions. Messenger RNA (mRNA) has emerged as a promising therapy for treating NDD, as it can encode missing or dysfunctional proteins and anti-inflammatory cytokines or neuroprotective proteins to halt the progression of these diseases. However, effective mRNA delivery to the central nervous system (CNS) remains a significant challenge due to the limited penetration of the blood-brain barrier (BBB). Lipid nanoparticles (LNPs) offer an efficient solution by encapsulating and protecting mRNA, facilitating transfection and intracellular delivery. This review discusses the pathophysiological mechanisms of neurological disorders, including Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), ischemic stroke, spinal cord injury, and Friedreich’s ataxia. Additionally, it explores the potential of LNP-mediated mRNA delivery as a therapeutic strategy for these diseases. Various approaches to overcoming BBB-related challenges and enhancing the delivery and efficacy of mRNA-LNPs are discussed, including non-invasive methods with strong potential for clinical translation. With advancements in artificial intelligence (AI)-guided mRNA and LNP design, targeted delivery, gene editing, and CAR-T cell therapy, mRNA-LNPs could significantly transform the treatment landscape for NDD, paving the way for future clinical applications.

Introduction

Neurodegenerative diseases (NDD), including Alzheimer’s disease (AD) [1], Parkinson’s disease (PD) [2], multiple sclerosis (MS) [3], and stroke [4], are leading causes of physical and cognitive disability worldwide [5]. The World Health Organization (WHO) predicts NDD will soon surpass cancer as the second leading cause of death, after cardiovascular diseases [5]. The prevalence of NDD is expected to double in the next two decades, yet limited understanding and lack of effective treatments remain major challenges. Future research should focus on NDD mechanisms, prevention, early diagnosis, effective treatment strategies, and improving long-term patient care [6,7].

Current treatment strategies for NDD primarily focus on symptom management through pharmacological and non-pharmacological interventions [7]. Among emerging approaches, RNA-based therapeutics, particularly messenger RNA (mRNA) therapy, show great promise by enabling targeted protein synthesis and identifying disease-related genes [8]. Synthetic mRNA allows efficient exogenous protein expression, rapid gene translation, and scalable production [5,9]. Compared to protein or other nucleic acid (NA)-based therapies, mRNA offers advantages such as controlled protein production, no risk of insertional mutagenesis, and functionality without nuclear entry [10].

Additionally, modifications to mRNA can enhance protein production while minimizing inflammatory responses [11,12]. A major challenge in mRNA-based therapy is ensuring that fragile mRNA molecules reach target cells intact without degradation [13]. Nanocarriers are crucial for protecting mRNA and enabling efficient delivery. Ideal carriers should encapsulate mRNA securely, maintain stability in circulation to prevent degradation by nucleases, and facilitate targeted cellular uptake and intracellular release. Additionally, they must be biocompatible, cost-effective, and easy to produce [14]. mRNA vectors are classified as viral and non-viral, with the latter offering greater flexibility, lower immunogenicity, and cost-effectiveness [15]. Non-viral delivery methods utilize biomaterials such as lipids, polymers, peptides, biomimetic membranes, and inorganic or metal-based carriers to gene transport [16]. Various lipid-based formulations, including liposomes, lipoplexes, cationic nanoemulsions (CNEs), nanostructured lipid carriers (NLCs), and lipid nanoparticles (LNPs) have been developed for NA delivery in neurological disorders [17]. Among them, LNPs are the most advanced non-viral mRNA carriers and have emerged as promising platforms for treating NDD [18].

Recognized as a breakthrough in non-viral drug delivery [19], LNPs enable the clinical application of genetic therapies by encapsulating mRNA, protecting it from enzymatic degradation, and ensuring efficient cellular uptake [20]. Potentially, they have the potential to encapsulate mRNA encoding missing or dysfunctional proteins, anti-inflammatory cytokines, immunomodulatory agents, and neuroprotective proteins to modify disease progression.

A major challenge in mRNA delivery to the central nervous system (CNS) in NDD treatment is overcoming the blood-brain barrier (BBB) [21]. The BBB is a highly selective semipermeable barrier that restricts the passage of large molecules, including nucleic acids, making gene delivery to the brain particularly difficult [22]. The exact mechanism of LNP-mediated mRNA delivery remains debated, but it is believed to involve endocytosis, electrostatic interactions, and fusion with the cell membrane through inverted non-bilayer lipid phases [23].

To overcome these challenges, several strategies can enhance mRNA delivery, effectiveness, and brain-targeting specificity. We explored various strategies including functionalizing LNPs with targeting ligand such as monoclonal antibodies, nanobodies [24,25], peptides [26], proteins [27], and small molecules [28] that specifically bind to receptors on the BBB. Additionally, we discussed techniques like focused ultrasound combined with microbubbles [[29], [30], [31]], as well as the use of mannitol [32,33] to temporarily disrupt the BBB and improve drug penetration. Modifying lipid components, incorporating multimeric mRNAs, and advanced RNA modalities (circular RNAs and self-amplifying RNAs) [34,35], may further enhance gene expression.

This review explores the potential of LNPs for mRNA-based therapies in treating NDD. It examines key challenges, opportunities, and strategies to enhance delivery, targeting specificity, effectiveness, and safety. Additionally, we discussed that advancements in artificial intelligence (AI)-guided mRNA/LNP design, targeted delivery, gene editing, and CAR-T cell therapy could develop treatments for NDD and enhance clinical applications of LNP-mediated mRNA therapies.

Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases

Abstract

Introduction

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