Targeting Multilayered Metabolic Networks in Brain Diseases: Emerging Perspectives on Nanodelivery Strategies
Time：2025/9/29 12:53:28 Views：90
Brain metabolism is uniquely regulated, and alterations in its metabolic networks often serve as critical drivers of the onset and progression of brain diseases. Therapeutic strategies that target these metabolic changes are regarded as fundamental to disease intervention. In complex metabolic networks, multi-level metabolic dysregulation typically initiates a shared pathological process: the disruption of core cell metabolism leads to impaired cell–cell interactions, ultimately promoting the development of a malignant microenvironment that supports disease progression. This process encompasses complex mechanisms such as substance transport, cell signaling, and the dynamic regulation of the microenvironment. Smart nanodelivery systems, with their versatility, responsiveness, and modularity, can precisely modulate these dynamic metabolic networks in brain diseases, guided by the underlying pathological mechanisms. In this review, the metabolic network characteristics associated with brain diseases is summarized and the use of nanodelivery systems and their combinations are explored for metabolic regulation, aiming to establish a novel therapeutic paradigm. The related work was published online in the prestigious international journal Advanced Science under the title “Targeting Multilayered Metabolic Networks in Brain Diseases: Emerging Perspectives on Nanodelivery Strategies.”
Although the brain accounts for only 2% of total body weight, it consumes approximately 20%–25% of the body's oxygen at rest, reflecting its exceptionally high metabolic demand. This vigorous metabolic activity is sustained by complex structural compartmentalization and diverse cellular populations, collectively forming a dynamic and finely tuned metabolic network. As a central regulatory interface, the blood–brain barrier (BBB) maintains cerebral metabolic homeostasis by selectively transporting essential substrates such as glucose, lipids, and amino acids. Once within the brain parenchyma, these substrates are metabolized by various cell types—particularly neurons, astrocytes, and microglia—through distinct intracellular pathways and intercellular coupling mechanisms, thereby supporting systemic metabolic stability.
Under pathological conditions, this metabolic network becomes disrupted at multiple levels. Intracellular metabolic imbalance, impaired energy exchange between cells, and perturbations in the metabolic microenvironment act synergistically to initiate a “pathological metabolic network” centered on metabolic reprogramming. This remodeled network drives the sustained progression of brain diseases. For instance, neurodegenerative diseases and brain tumors often exhibit a similar pathological pattern: aberrant glucose metabolism in key cells impairs the metabolic functionality of neighboring populations, reshaping the microenvironment and exacerbating disease progression through positive feedback loops.
Abnormal metabolism thus represents not only a hallmark of brain disorders but also a central driving force behind their development, making it an increasingly important target for diagnosis and therapy. Clinically, positron emission tomography (PET) using fluorine-18-labeled fluorodeoxyglucose (18F-FDG) has become a widely adopted technique for early diagnosis and lesion localization in various brain diseases, as it provides a direct assessment of glucose metabolic abnormalities . Despite advances in small-molecule drugs aimed at modulating brain metabolism, several major obstacles remain. First, the BBB poses a significant barrier to the efficient delivery and accumulation of therapeutic agents at the lesion site, limiting drug efficacy. Second, the intricate and region-specific intercellular networks in the brain are difficult to precisely modulate using conventional pharmacological approaches, which may instead trigger widespread metabolic disruption and compromise vital physiological functions. Moreover, the metabolic pathways of the brain are characterized by high degrees of coupling and dynamic compensation, making it difficult for single-target interventions to align with the underlying pathological complexity, often resulting in limited clinical benefit.
In this context, smart nano-delivery systems offer promising solutions. Through rational design, nanocarriers can significantly enhance drug penetration across the BBB and enable cell-specific targeting, thereby achieving multi-level and multi-process metabolic intervention. Such systems can co-deliver multiple therapeutic agents to simultaneously modulate intracellular metabolism, intercellular metabolic interactions, and the surrounding microenvironment, achieving coordinated multi-target regulation. Some functional nanomaterials even possess intrinsic therapeutic activities, and their capacity for spatiotemporal control over drug release allows for adaptive responses to the evolving pathological metabolic landscape.
Based on these considerations, this review systematically summarizes recent advances in nano-delivery strategies for regulating brain metabolism, focusing on their potential for multi-target delivery and complex network interventions, while integrating the characteristic metabolic features of brain diseases. This work provides valuable theoretical and practical guidance for the development of nano-enabled diagnostic and therapeutic approaches for brain disorders.
Jingyi Zhou , a doctoral candidate in this research group, is the first author of the paper, and Professor Chen Jiang is the corresponding author.
This study was supported by the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Major Project, the Pingyuan Laboratory Open Fund, and the Zhangjiang Laboratory.
Original link:
https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202503645
