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生物大分子药物的脑递送策略：鼻内给药

Brain Delivery Strategies for Biomacromolecular Drugs: Intranasal Administration.

作者信息

Wu Huanhuan, Li Chenyu, Yuan Hong, Zhao Jingyuan, Li Shuai

机构信息

The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.

Dalian Medical University, Dalian, People's Republic of China.

出版信息

Int J Nanomedicine. 2025 May 22;20:6463-6487. doi: 10.2147/IJN.S520768. eCollection 2025.

DOI:10.2147/IJN.S520768
PMID:40420915
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12105674/
Abstract

Macromolecular Drugs (including monoclonal antibodies, recombinant proteins, and nucleic acid therapies) have become a cornerstone strategy for intervening in complex pathological mechanisms such as cancer, autoimmune diseases, and genetic disorders due to their high specificity for disease targets and low off-target toxicity. However, compared to traditional small-molecule drugs, the high molecular weight (>10 kDa) and structural complexity of macromolecular drugs result in extremely low transmembrane permeability. This is particularly challenging in the treatment of central nervous system (CNS) diseases, where the blood-brain barrier (BBB) imposes stringent selectivity, further limiting drug delivery efficiency. This review focuses on the breakthrough strategy of nose-to-brain (NtB) drug delivery. On one hand, the NtB pathway bypasses the BBB, enabling direct CNS drug delivery. On the other hand, nanocarrier technology can synergistically achieve systemic delivery and brain-targeted transport. Based on the latest research advances, this article systematically examines the feasibility of delivering macromolecular drugs via NtB administration. We comprehensively summarize relevant delivery carriers and discuss the potential advantages of intranasal-brain delivery for CNS disease treatment. Notably, while significant progress has been made in this field, further exploration is still needed regarding the mechanisms of NtB delivery and challenges in clinical translation.

摘要

大分子药物（包括单克隆抗体、重组蛋白和核酸疗法）因其对疾病靶点的高特异性和低脱靶毒性，已成为干预癌症、自身免疫性疾病和遗传疾病等复杂病理机制的基石策略。然而，与传统小分子药物相比，大分子药物的高分子量（>10 kDa）和结构复杂性导致其跨膜通透性极低。这在中枢神经系统（CNS）疾病的治疗中尤其具有挑战性，因为血脑屏障（BBB）具有严格的选择性，进一步限制了药物递送效率。本综述重点关注鼻脑（NtB）给药的突破性策略。一方面，NtB途径绕过了血脑屏障，实现了中枢神经系统药物的直接递送。另一方面，纳米载体技术可以协同实现全身递送和脑靶向运输。基于最新的研究进展，本文系统地研究了通过NtB给药递送大分子药物的可行性。我们全面总结了相关的递送载体，并讨论了鼻内脑递送在中枢神经系统疾病治疗中的潜在优势。值得注意的是，虽然该领域已取得重大进展，但在NtB递送机制和临床转化挑战方面仍需进一步探索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7351/12105674/9de278dc5c32/IJN-20-6463-g0011.jpg
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Engineered commensals for targeted nose-to-brain drug delivery.用于靶向鼻脑给药的工程共生菌。
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Intranasal delivery of mesenchymal stem cell-derived exosomes ameliorates experimental autoimmune encephalomyelitis.间充质干细胞衍生外泌体的鼻内递送可改善实验性自身免疫性脑脊髓炎。
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