药学学报

Peptide	Target	Indication	Stage	Outcome	Ref.
NGR	CD13	Tumor neo-vasculature	Phase 1	The fusion protein tTF-NGR can be safely applied to patients with advanced cancer with good tolerability	[29]
TAT	JNK	Idiopathic sudden sensorineural hearing loss	Phase 3	AM-111 in a broad range of ototraumatic conditions	[30]
P28	VEGFR-2	Repeated or progressive high grade glioma	Phase 2	P28 enhances the cell cycle inhibition and reduces tumor cell proliferation	[31]
KGF	FGFR2b	Acute respiratory distress syndrome	Phase 2	KGF was not beneficial for physiological outcomes in ARDS and could make clinical outcomes worse	[32]
RGD	Integrin αvβ3	Neuroendocrine neoplasms	Phase 2	Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)]2 was evident in patients with all grades of NEN	[33]
CHP	NRCMs	Cardiac hypertrophy	Preclinical	Targeted ischemia/reperfusion injury of myocardial tissue, improve cardiac function	[34]
RVG29	nAchR	Alzheimer's disease	Preclinical	Enhance cell uptake and brain targeting performance	[35]

Peptide

Target

Indication

Stage

Outcome

Ref.

NGR

CD13

Tumor neo-vasculature

Phase 1

The fusion protein tTF-NGR can be safely applied to patients with advanced cancer with good tolerability

[29]

TAT

JNK

Idiopathic sudden sensorineural hearing loss

Phase 3

AM-111 in a broad range of ototraumatic conditions

[30]

P28

VEGFR-2

Repeated or progressive high grade glioma

Phase 2

P28 enhances the cell cycle inhibition and reduces tumor cell proliferation

[31]

KGF

FGFR2b

Acute respiratory distress syndrome

Phase 2

KGF was not beneficial for physiological outcomes in ARDS and could make clinical outcomes worse

[32]

RGD

Integrin αvβ3

Neuroendocrine neoplasms

Phase 2

Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)]2 was evident in patients with all grades of NEN

[33]

CHP

NRCMs

Cardiac hypertrophy

Preclinical

Targeted ischemia/reperfusion injury of myocardial tissue, improve cardiac function

[34]

RVG29

nAchR

Alzheimer's disease

Preclinical

Enhance cell uptake and brain targeting performance

[35]

Peptide	Target	Indication	Stage	Outcome	Ref.
NGR	CD13	Tumor neo-vasculature	Phase 1	The fusion protein tTF-NGR can be safely applied to patients with advanced cancer with good tolerability	[29]
TAT	JNK	Idiopathic sudden sensorineural hearing loss	Phase 3	AM-111 in a broad range of ototraumatic conditions	[30]
P28	VEGFR-2	Repeated or progressive high grade glioma	Phase 2	P28 enhances the cell cycle inhibition and reduces tumor cell proliferation	[31]
KGF	FGFR2b	Acute respiratory distress syndrome	Phase 2	KGF was not beneficial for physiological outcomes in ARDS and could make clinical outcomes worse	[32]
RGD	Integrin αvβ3	Neuroendocrine neoplasms	Phase 2	Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)]2 was evident in patients with all grades of NEN	[33]
CHP	NRCMs	Cardiac hypertrophy	Preclinical	Targeted ischemia/reperfusion injury of myocardial tissue, improve cardiac function	[34]
RVG29	nAchR	Alzheimer's disease	Preclinical	Enhance cell uptake and brain targeting performance	[35]

Peptide

Target

Indication

Stage

Outcome

Ref.

NGR

CD13

Tumor neo-vasculature

Phase 1

The fusion protein tTF-NGR can be safely applied to patients with advanced cancer with good tolerability

[29]

TAT

JNK

Idiopathic sudden sensorineural hearing loss

Phase 3

AM-111 in a broad range of ototraumatic conditions

[30]

P28

VEGFR-2

Repeated or progressive high grade glioma

Phase 2

P28 enhances the cell cycle inhibition and reduces tumor cell proliferation

[31]

KGF

FGFR2b

Acute respiratory distress syndrome

Phase 2

KGF was not beneficial for physiological outcomes in ARDS and could make clinical outcomes worse

[32]

RGD

Integrin αvβ3

Neuroendocrine neoplasms

Phase 2

Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)]2 was evident in patients with all grades of NEN

[33]

CHP

NRCMs

Cardiac hypertrophy

Preclinical

Targeted ischemia/reperfusion injury of myocardial tissue, improve cardiac function

[34]

RVG29

nAchR

Alzheimer's disease

Preclinical

Enhance cell uptake and brain targeting performance

[35]

细胞穿膜肽与归巢肽修饰纳米载体突破生理屏障的研究进展

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李芳 , 黄丽珍 , 胡文慧 , 邹海滨 , 岳鹏飞 , 陈颖翀 ^*

药学学报 | 综述 2026,61(5): 1610-1622

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药学学报 |综述 2026 , 61 (5) : 1610 -1622

细胞穿膜肽与归巢肽修饰纳米载体突破生理屏障的研究进展

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李芳, 黄丽珍, 胡文慧, 邹海滨, 岳鹏飞, 陈颖翀^*

作者信息

江西中医药大学, 现代中药制剂教育部重点实验室, 江西南昌 330004

通讯作者:

陈颖翀, Tel: 86-791-87118658, E-mail: yc_chen1020@163.com

作者简介:

作者贡献:

李芳负责文献调研与文章撰写; 黄丽珍、胡文慧、邹海滨负责文章排版与文献整理; 岳鹏飞负责对文章进行指导完善; 陈颖翀负责文章选题建议、思路设计与文章修改。

Advances in cell penetrating peptides and homing peptides modified nanocarriers for overcoming the physiological barrier

Fang LI, Li-zhen HUANG, Wen-hui HU, Hai-bin ZOU, Peng-fei YUE, Ying-chong CHEN^*

Affiliations

Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China

出版时间: 2026-05-12 doi: 10.16438/j.0513-4870.2025-1069

文章导航

摘要

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纳米载体作为新型给药系统, 在提高药物溶解度、稳定性及靶向性方面展现出显著的优势, 已成为当前药物递送领域的研究热点。然而, 其穿透细胞膜及跨越机体多重生理屏障的能力有限, 严重制约了临床应用效果。细胞穿膜肽(cell-penetrating peptides, CPPs) 因其具有高穿膜效率、低毒性及良好的生物相容性特点, 可通过直接渗透或内吞途径有效促进纳米载体穿透生物膜屏障, 显著提升药物递送效率; 归巢肽(homing-peptide, HPs) 则能通过识别靶组织特异性受体, 精准介导纳米载体靶向富集于病变部位, 减少对正常组织的非特异性穿透。因此, CPPs与HPs作为两类重要的功能性多肽, 通过不同机制增强纳米载体的生理屏障跨越能力和病变部位靶向富集效率, 已被广泛应用于纳米载体修饰。本文从CPPs与HPs分类、转运机制和CPPs与HPs修饰纳米载体突破生理屏障进行概述, 为今后CPPs与HPs的相关研究应用提供参考。

关键词

纳米载体 / 细胞穿膜肽 / 归巢肽 / 分类 / 转运机制 / 生理屏障

Abstract

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Nanocarriers, have been extensively explored as a novel drug delivery system, demonstrating significant advantages in improving drug solubility, stability, and targeting capability, and have thus become a research focus in the field. However, their clinical application is substantially limited by a poor capacity to traverse cellular membranes and overcome complex physiological barriers. Cell-penetrating peptides (CPPs), characterized by high membrane penetration efficiency, low toxicity, and favorable biocompatibility, can effectively facilitate the translocation of nanocarriers across biological membrane barriers via direct penetration or endocytosis, thereby significantly enhancing drug delivery efficiency. Concurrently, homing peptides (HPs) enable precise accumulation of nanocarriers at pathological sites by recognizing tissue-specific receptors, while reducing non-specific penetration into healthy tissues. As two crucial classes of functional peptides, CPPs and HPs have been widely utilized to modify nanocarriers, enhancing their capacity to overcome physiological barriers and improving targeted accumulation at diseased sites through distinct mechanisms. This review summarizes the classification and transport mechanisms of CPPs and HPs, as well as advances in their application for modifying nanocarriers to overcome physiological barriers, aiming to provide a reference for future research and applications in this field.

Key words

nanocarrier / cell penetrating peptide / homing peptide / classification / transport mechanism / physiological barrier

引用本文

李芳, 黄丽珍, 胡文慧, 邹海滨, 岳鹏飞, 陈颖翀. 细胞穿膜肽与归巢肽修饰纳米载体突破生理屏障的研究进展. 药学学报, 2026 , 61 (5) : 1610 -1622 . DOI: 10.16438/j.0513-4870.2025-1069

Fang LI, Li-zhen HUANG, Wen-hui HU, Hai-bin ZOU, Peng-fei YUE, Ying-chong CHEN. Advances in cell penetrating peptides and homing peptides modified nanocarriers for overcoming the physiological barrier[J]. Acta Pharmaceutica Sinica, 2026 , 61 (5) : 1610 -1622 . DOI: 10.16438/j.0513-4870.2025-1069

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药物在体内的有效递送是其发挥治疗作用的前提。然而, 此过程面临血脑屏障、黏膜屏障、皮肤屏障等多重生理屏障的严峻挑战^[1]。这些屏障通过限制药物扩散、介导外排及酶解等机制, 显著降低了药物靶向递送效率与生物利用度, 从而严重制约其治疗效果^[2]。血脑屏障凭借紧密连接的内皮细胞和高表达的外排转运蛋白, 可阻止约98%的小分子药物及几乎全部的大分子药物进入中枢神经系统^[3]; 而黏液屏障则通过黏液层的动态黏附与酶解作用, 使药物难以有效抵达上皮细胞表面^[4]。因此, 如何设计能够高效、精准地突破这些生理屏障的药物递送系统, 已成为现代药学研究的核心前沿问题。

纳米载体作为粒径介于1~1 000 nm的药物递送系统, 为克服上述挑战提供了可能^[5]。其独特的纳米尺寸效应赋予了优异的递送潜力: 一方面, 较小的粒径使其可通过增强渗透与滞留(enhanced permeation and etention, EPR) 效应实现被动富集^[6]; 另一方面, 其表面易于修饰功能配体, 通过靶向结合特定受体介导纳米载体主动跨越屏障。然而, 未经修饰的纳米载体在复杂的体内环境中仍面临多重挑战: 其结构的不稳定易导致药物提前泄漏; 部分纳米载体材料的潜在免疫原性可能引发全身性免疫反应^[7]。此外, 其主要依赖EPR效应的被动靶向方式靶向特异性不足, 尤其是在非肿瘤性疾病的治疗和跨越其他生理屏障时效率低下^[8]。因此, 对纳米载体进行功能化修饰, 以提升其靶向特异性与跨屏障能力, 已成为解决上述局限性的迫切需求。

其中, 多肽修饰是改善纳米载体靶向性、生物相容性及跨屏障能力的关键策略之一。多肽是由10~50个氨基酸组成的短链生物分子^[9], 具有易合成、易代谢、毒性低等优点, 在药物递送、疾病诊断与生物材料领域展现出巨大的应用潜力。其中, 细胞穿膜肽(cell-penetrating peptides, CPPs) 和归巢肽(homing-peptide, HPs) 是两种研究最为广泛的功能性多肽。二者通过不同的作用机制优化纳米载体的体内行为, 从而协同促进纳米载体高效突破生理屏障, 实现精准递送。

CPPs是一类5~30个氨基酸残基组成的具有穿膜活性的短肽。凭借其穿膜效率高、细胞毒性低及对所携带生物活性分子尺寸与剂量限制小等优势^[10], CPPs被广泛应用于癌症、脑卒中及病毒或细菌感染等多种疾病的诊断、治疗及预后评估。同时其在促进纳米载体跨越屏障, 实现药物递送方面展现出巨大潜力^[11]。HPs则是一类可特异性识别并结合肿瘤、心脏、肌肉等组织中过表达受体的多肽。其靶向能力源于与靶点的高亲和力, 而该亲和力取决于肽链的二级结构, 如α螺旋、β折叠或无规则卷曲^[12]。通过受体介导的主动靶向机制, HPs可将纳米载体精准递送至病灶部位, 在有效提高局部药物浓度的同时, 显著降低对正常组织的脱靶效应和全身性毒副作用^[13]。

近年来, 将CPPs或HPs用于修饰纳米载体的策略已成为药物递送领域的研究热点。本文旨在系统综述CPPs与HPs的研究进展, 首先构建了一个更为精细的分类体系, 该系统不仅涵盖了CPPs的经典分类, 更依据靶向组织的生理/病理状态对HPs进行了细分, 并整合了兼具穿膜与归巢双重功能的穿膜归巢肽(cell penetrating homing peptides, CPHPs)。围绕这一分类框架, 进一步阐述了其修饰的纳米载体在突破生理屏障方面的转运机制、连接策略及最新研究进展, 旨在为该领域研究者提供一个更具结构化和前瞻性的理论参考。

1　CPPs及HPs的分类

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1.1　CPPs分类

CPPs的分类方法多样: 根据其来源分为天然肽和合成肽; 根据氨基酸的类型及排列方式, 可分为阳离子肽、阴离子肽、两亲性肽和疏水性肽; 根据细胞毒性差异, 可分为无毒型和抗菌型; 根据空间结构特征, 则分为环状肽和线状肽^[14]。在众多分类方法中, 基于氨基酸序列、疏水性及带电荷的分类方法, 因其能将CPPs的理化性质与作用机制紧密关联, 对于修饰纳米载体的理论设计具有指导意义。例如, 阳离子CPPs可凭借静电相互作用介导跨膜转运; 而两亲性CPPs可通过两亲性α螺旋结构实现跨膜转运^[15]。因此, 本文主要采用此方法, 将CPPs分为阳离子型、两亲性及疏水性3类。这一分类方式不仅有助于系统性地理解不同CPPs的构效关系, 也为理论设计和优化CPPs修饰的纳米载体提供了清晰的理论框架。

1.1.1　阳离子CPPs

阳离子CPPs主要由精氨酸(Arg, R) 和赖氨酸(Lys, K) 等带正电荷的氨基酸组成, 在生理pH条件下, 这些碱性氨基酸残基发生质子化, 使CPPs携带高密度正电荷。该强正电性是其介导跨膜转运的关键, 能够促进其与细胞膜表面带负电荷的糖胺聚糖(glycosaminoglycans, GAGs) 等组分发生静电相互作用, 通过细胞内化实现跨膜转运^[16]。

该类CPPs的典型代表包括: ① HIV-1的反式激活蛋白TAT的核心片段(TAT49-57): 该片段可通过上述静电作用与细胞膜表面糖胺聚糖结合, 从而高效介导跨膜转运^[17]; ②多聚精氨酸肽: 此类多肽凭借其强阳离子特性, 在跨越血脑屏障等致密生理屏障方面展现卓越潜力^[18]。其细胞摄取效率通常随精氨酸残基链长的增加而提高。然而, 当数量超过8~10个残基时, 可能因易位作用导致细胞膜损伤。因此, 含有8~10个残基的多聚精氨酸(如R8肽) 被普遍认为是实现穿膜效率与生物安全性平衡的优化设计^[19]。

1.1.2　两亲性CPPs

两亲性CPPs由亲水性和疏水性氨基酸交替排列而成, 其两亲性特征可通过一级序列直接体现, 或通过空间折叠形成具有亲水性和疏水性界面的α螺旋结构实现^[20]。这类CPPs多为嵌合肽, 通过共价键将疏水结构域与核定位信号连接, 兼具膜穿透能力与胞内定位功能。

该类CPPs的典型代表包括: ①转运蛋白肽(transportan, TP): 其N端疏水片段源自胃泌素释放肽, C端亲水片段源自富含阳离子残基蜂毒明肽。在细胞膜环境中可形成两亲性α螺旋构象, 通过插入并瞬时扰动脂质双层结构, 从而介导分子跨膜递送^[21]; ② Pep-1肽: 通过疏水结构域与载体结合, 阳离子区域介导细胞内化, 在递送蛋白质类药物跨越细胞膜屏障中应用广泛, 并展现出良好的载体适配性^[22]。

1.1.3　疏水性CPPs

疏水性CPPs主要来源于蛋白质信号肽序列, 这些序列不仅介导蛋白质的分泌, 其固有的疏水性也能促进大分子跨细胞内化。目前鉴定的疏水转导肽的例子包括角质形成细胞生长因子(keratinocyte growth factor, KGF) 和成纤维细胞生长因子的前导序列, 研究表明, 许多分泌蛋白的前导序列均具备穿膜功能^[23]。与阳离子及两亲性CPPs不同, 疏水性CPPs的穿膜是通过其疏水结构直接插入并扰动脂质双分子层的有序性, 从而实现跨膜转运。此类CPPs的典型代表为KGF的前导序列, 可介导蛋白质逆浓度梯度跨越上皮细胞屏障^[24]。

1.2　HPs分类

HPs是一类能特异性识别并结合特定组织或细胞表面受体的短肽。其核心优势在于主动靶向性: 通过“受体-配体”特异性相互作用, 能够使药物或纳米载体精准富集于目标部位, 显著降低非特异性分布, 从而为药物递送提供了一种高效且安全的策略^[25]。HPs的分类主要依据其靶向的组织类型及功能特征。

1.2.1　肿瘤归巢肽

1996年, Ruoslahti等^[26]首次通过噬菌体展示技术筛选出组织特异性HPs, 证实了其可将药物靶向递送至高表达特定受体的组织器官。其中, 肿瘤归巢肽(tumor homing peptides, THPs) 因能特异性识别肿瘤微环境, 在提升抗肿瘤药物疗效、降低全身毒副作用方面展现出巨大潜力, 已成为该领域的研究热点。这类短肽主要靶向肿瘤血管内皮细胞或肿瘤细胞表面的过表达的特异性受体, 通过受体介导的识别作用, 促进药物有效突破肿瘤血管屏障^[27]。

此类HPs的典型代表包括: ① RGD肽: 其核心三肽序列能与肿瘤血管内皮细胞高表达的整合素αvβ3特异性结合, 介导纳米载体向肿瘤组织的精准靶向^[28]; ② NGR肽: 该肽通过识别肿瘤新生血管表面标志物CD13受体, 在增强药物向肿瘤递送方面效果显著。基于该肽的靶向修饰制剂已进入临床I/II期试验, 且展现出良好的耐受性^[29]。表1^[29-35]列举了部分CPPs/HPs临床研究。

1.2.2　CPHPs

CPHPs是一类兼具靶向识别与跨膜穿透双重功能的多肽^[36], 旨在实现药物递送的“先寻靶, 后入胞”。根据其来源和构建方式, 主要分为两类: ①天然存在的CPHPs: 此类肽本身同时具备与特定受体结合及细胞穿透能力, 通过受体介导的内吞作用进入细胞, 其穿膜能力是自身固有的理化性质和内化共同作用的结果^[37]。Keller等^[36]鉴定出的CPHPs——HGDWT肽, 修饰溶酶素(lysostaphin, LST) 用于靶向治疗葡萄球菌性骨髓炎。实验结果表明, LST-HGDWT显著降低了1.2 log单位的受感染骨骼中的细菌载量, 与未经修饰的LST相比增加了50%; ②人工合成的CPHPs: 通过化学等方法将CPPs与HPs偶联, 从而兼具双重功能。Myrberg等^[38]将pVES (CPPs) 肽与THPs肽结合, 构建的CPHPs显著增强了在肿瘤细胞中的内化效率, 显著提升了对肿瘤细胞的选择性, 有效解决了单一CPPs靶向性不足的缺陷。

1.2.3　组织特异性HPs

除肿瘤靶向外, HPs还能够特异性识别心脏、肌肉、血管等正常组织的标志性受体, 这种精准识别能力在突破组织特异性生理屏障方面发挥重要作用, 为治疗多种非肿瘤性疾病的靶向治疗提供了新策略。

1.2.3.1　心脏归巢肽

心脏归巢肽(cardiac homing peptides, CHPs) 是一类能够优先与缺血心肌组织结合的短肽^[39]。研究表明, 经CHPs修饰的外泌体不仅能被体外心肌细胞内化, 更能靶向体内缺血/再灌注损伤心肌组织, 进而增强血管新生, 减少细胞凋亡和纤维化, 最终改善心脏功能^[34]。

Wang等^[39]构建了负载葛根素(puerarin, PUE) 的硫酮醛(thioketal, TK) 和CHP双修饰的ROS响应脂质体, 用于治疗心肌缺血再灌注损伤。结果显示, 与香豆素-6 (coumarin-6, C6) 相比, 缺氧/复氧(H/R) 损伤的H9c2细胞对C6@CHP-L和C6@TK/CHP-L的细胞摄取在1 h内分别增加了2.6和2.7倍, 表明CHP有助于H/R损伤的H9c2细胞对脂质体的摄取。

1.2.3.2　肌肉归巢肽

肌肉归巢肽(muscle homing peptides, MHPs) 是一类可特异性识别骨骼肌细胞表面特征性抗原, 从而介导纳米载体精准靶向肌肉组织并突破肌膜屏障的功能性短肽^[40]。MHPs的应用为衰老相关肌萎缩、肌营养不良等肌肉疾病的靶向给药提供新策略。

以M12肽为典型代表, Xie等^[41]构建了M12修饰负载姜黄素(curcumin, Cur) 的仿生纳米晶(M12-MNCs), 用于治疗衰老性骨骼肌萎缩。研究结果表明, 与未经修饰的纳米晶相比, M12-MNCs使骨骼肌细胞对姜黄素的摄取率提高了39.09%, 且M12-MNCs的t_1/2和AUC_0-t值分别提高了2.05和1.45倍, 表明M12肽修饰可显著增强纳米载体的肌肉靶向效率及药物的体内滞留能力。

1.2.3.3　血管归巢肽

血管归巢肽(vascular homing peptide, CARs) 是一类可特异性识别血管内皮细胞表面标志物的短肽, 尤其是对新生血管或炎症状态下血管内皮的异常表达标志物具有高亲和力^[42]。其中, CAR肽与CRK肽因对伤口血管的高选择性, 又被称为“伤口归巢肽”。近年来研究进一步证实, CAR肽不仅能靶向新生血管, 还可识别肺动脉高压、心肌梗死和主动脉瘤等疾病中的炎症病灶, 这与其能结合炎症状态下血管内皮细胞异常表达的受体有关^[43]。

Maldonado等^[42]发现CAR肽可通过结合syndecan-4激活下游ARF6信号通路, 进而促进内源性SDC4的表达, 加速生理性伤口修复。Iqbal等^[44]利用CAR肽的靶向性, 将其与核心蛋白肽(天然TGFβ抑制剂) 偶联用于治疗肌营养不良症。经过3周的干预, 该靶向治疗策略成功将药物递送至骨骼肌, 不仅降低了肌纤维膜通透性与组织纤维化, 更改善了骨骼肌功能。

1.2.3.4　脑归巢肽

脑归巢肽(brain homing peptide, BHPs) 是一类能够特异性靶向中枢神经系统的短肽^[45]。其中, 以狂犬病毒糖蛋白RVG29肽为典型代表, 通过特异性结合神经元表面的烟碱型乙酰胆碱受体, 介导纳米载体跨越血脑屏障并靶向神经元^[46]。Pinheiro等^[47]构建了RVG29肽修饰的槲皮素脂质纳米颗粒。研究结果显示, 该功能化纳米粒在体外血脑屏障模型中的通透性与未经修饰组比较提高了1.5倍, 表明RVG29肽能有效增强药物在脑部的递送。

此外, Dong等^[48]构建了由脑卒中归巢肽(stroke homing peptide, SHp) 修饰的ROS响应仿生纳米颗粒, 用于缺血性脑卒中治疗。结果显示, 经SHp肽修饰的纳米粒能更快地富集于受损脑组织, 靶向效率比 β-环糊精对照组提升了5.68倍。表明SHp作为一种新型HPs, 能够有效地引导纳米载体快速、精准地递送到病灶, 为脑卒中等急性神经损伤的靶向治疗提供了新的可能。

2　CPPs及HPs修饰纳米载体的转运机制

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2.1　CPPs修饰纳米载体的转运机制

CPPs修饰的纳米载体主要通过以下两种途径跨越细胞膜: 能量依赖性的内吞作用(endocytosis) 和非能量依赖性的直接渗透(direct penetration)。这两种机制并非完全独立, 在特定条件下可能存在协同作用, 共同调控纳米载体的跨膜转运效率(图1)。

2.1.1　内吞作用

内吞作用是CPPs介导纳米载体内化的主要能量依赖性途径。根据其分子机制的不同, 分为两类^[49]: ①网格蛋白的内吞: CPPs与细胞膜受体结合后, 可招募网格蛋白并促使有被小窝的形成, 随后有被小窝内陷并脱落形成囊泡, 将纳米载体转运至细胞内。该途径具有较高的受体特异性和选择性, 是CPPs修饰纳米载体跨越血脑屏障等生理屏障的重要机制之一; ②非网格蛋白的内吞: 此类途径不依赖网格蛋白, 其机制更为多样, 涉及胞膜窖蛋白、肌动蛋白等多种分子。该途径适用于递送脂质体等大尺寸纳米载体跨越肿瘤间质屏障。

2.1.2　直接渗透

直接渗透是一种非能量依赖且不涉及特定膜蛋白介导的穿膜方式。包括3种经典模型: ①瞬时孔道模型: 带正电荷的CPPs通过静电作用富集于带负电的膜表面, 与磷脂头的多氢键相互作用诱导膜结构发生瞬时弯曲, 形成跨膜孔道, 在此过程中, CPPs的疏水区与膜脂疏水核心相互作用, 而亲水区则构成孔道内壁, 为亲水性物质的跨膜转运提供通道^[50]; ②地毯模型: CPPs以地毯方式平行覆盖于膜表面, 通过电荷相互作用破坏磷脂头基的有序排列, 增加膜流动性并导致局部膜变薄, 最终使CPPs穿透脂质双层; ③倒置胶束模型: CPPs诱导局部脂质双层发生重排, 形成将CPPs包裹在内的倒置胶束结构。随后, 该胶束结构发生翻转, 将CPPs从膜外释放至胞内^[51]。

尽管CPPs可通过内吞作用或直接渗透两种主要途径进入细胞, 但内体逃逸效率低下, 是制约CPPs介导的纳米载体递送效率的关键因素。多数情况下, CPPs经由内吞途径进入细胞后, 转运途径包括内化为内吞囊泡、与早期内体融合、成熟为晚期内体及溶酶体中积累^[52], 如果不能迅速从溶酶体中逃逸将会被其降解。促进溶酶体逃逸策略主要分为: 质子海绵效应、膜不稳定性、膜融合和膜破坏^[53]。尽管策略多样, 但如何平衡逃逸效率与细胞毒性及实现精准可控的逃逸, 仍是当前研究的重点与难点。

2.2　HPs修饰纳米载体的转运机制

HPs修饰的纳米载体以内吞作用为主要入胞途径, 该过程由HPs与细胞表面特异性受体的高亲和力结合。具有ATP依赖性及主动靶向性, 其内化效率受血清等非特异性蛋白的影响较小, 这与CPPs的非特异性穿膜特性形成显著差异^[27]。具体而言, 内吞途径取决于HPs的类型及靶受体的特性, 主要包括网格蛋白介导内吞、小窝介导的内吞及巨胞饮作用^[54]。

HPs的靶向转运始于与靶细胞表面受体的特异性结合, 该过程具有高度的组织与细胞选择性。THPs中, 整合素在肿瘤细胞上高度表达, 是肿瘤靶向治疗的常用靶点。iRGD肽在与整合素结合后发生蛋白水解, 暴露出C末端的CendR基序与细胞表面NRP-1受体结合, 通过网格蛋白介导的内吞途径进入肿瘤细胞^[55]; LyP-1肽是一种环9-氨基酸肽, 可特异性结合乳腺癌、骨肉瘤、前列腺癌及肿瘤相关巨噬细胞表面p32/gC1qR受体, 同样由网格蛋白介导的内吞实现细胞内化^[56]。这两种肽的转运过程均体现了HPs依赖“受体-内吞”通路的靶向转运特性。

HPs的靶向性高度依赖于与表面特异性受体的结合。然而, 这些靶点受体在不同患者、同一患者不同病灶或同一肿瘤内部的不同细胞间, 其表达水平都存在显著差异^[57]。这种差异性限制了单一HPs靶向策略的普适性。因此, 需要在发展个性化靶向方案和优化HPs协调递药等方面持续探索, 以实现高效、精准药物递送。

3　CPPs及HPs修饰纳米载体

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纳米载体(nanocarriers) 是粒径通常介于1~1 000 nm之间的新型药物递送系统, 包括脂质体、胶束、纳米晶体和无机纳米粒等。该类载体凭借纳米尺寸效应, 在改善药物溶解度、药物稳定性及降低全身毒性方面展现出显著优势, 并能通过实体瘤的高通透性和EPR效应实现被动靶向富集^[6]。然而, 未经修饰的纳米载体在跨越复杂生理屏障方面仍存在细胞穿透能力不足等明显局限, 导致所载的药物难以有效到达靶部位并发挥疗效^[58]。

研究表明, 通过CPPs或HPs对纳米载体表面进行修饰, 是增强其屏障穿透能力与组织特异性的有效策略, 可用于构建高效的靶向递药系统^[59]。其中, CPPs修饰主要赋予纳米载体强大的细胞膜穿透能力, 以促进药物的胞内递送; 而HPs则赋予纳米载体组织或细胞特异性, 通过受体介导实现“靶向富集-高效入胞”的协同效应。这种多肽修饰策略为构建高效、精准的跨屏障递送系统提供了一种新的思路(图2)。

3.1　CPPs及HPs修饰脂质体

脂质体(liposome) 是由胆固醇和磷脂制成类似生物膜的纳米球形囊泡, 其粒径通常介于2.5~500 nm之间。凭借其良好生物相容性、独特的“核-壳”结构及可利用EPR效应在肿瘤部位被动富集的特点, 脂质体已成为应用最广泛的药物递送平台^[60]。然而, 未经修饰的脂质体在体内递送过程中仍面临严峻挑战: ①结构稳定性差: 磷脂双分子层易因温度波动、离子强度变化发生融合或破裂, 导致包载药物提前泄漏, 实际载药效率与体内循环时间显著降低^[61]; ②缺乏主动靶向性: 仅依赖EPR效应的被动靶向易受肿瘤血管通透性差异影响, 导致肝、脾等正常组织非特异性蓄积^[62], 难以实现“病灶精准递送”, 无法满足精准治疗需求。

研究表明, 多肽修饰为解决上述问题提供了有效策略。Ahmed等^[63]为克服乳腺癌的多柔比星耐药性, 制备了经R8肽修饰共载盐酸多柔比星(doxorubicin, DOX) 和塞来昔布(celecoxib, CEL) 的脂质体。结果显示, 经R8肽修饰的脂质体的平均荧光强度分别比DOX/CEL脂质体、DOX脂质体和DOX溶液强约1.41、2.74和5.72倍, 表现出更强的细胞内化能力。

Xu等^[64]则构建了由cRGD环肽修饰共载氯素e6与DOX脂质体, 用于肝细胞癌治疗。体内抗肿瘤研究表明, 经cRGD肽修饰的脂质体抑瘤率达94%, 且表现出较高的生物安全性和卓越的抗肿瘤功效。

3.2　CPPs及HPs修饰纳米晶体

纳米晶体(nanocrystal) 由药物与少量表面活性剂构成, 载药量高达40%~90%, 但其存在表面能高易于聚集、难以有效穿透生理屏障等缺陷^[65]。采用CPPs或HPs修饰对纳米晶体进行表面修饰, 可同时解决其稳定性与穿透性问题。

Huang等^[66]构建了由RGD肽修饰聚乙二醇(polyethylene glycol, PEG) 化紫杉醇纳米晶, 用于肺癌。研究结果表明, 与未经修饰的纳米晶相比, 经RGD肽修饰的细胞摄取提高约1.7倍, 肿瘤内药物蓄积提升了2.3倍, 表明RGD肽可增强纳米晶递送的靶向性。

3.3　CPPs及HPs修饰量子点

量子点(quantum dots, QD) 是一类具有强荧光特性、低光散射及低组织吸收的半导体纳米晶。自1998年首次应用于生物成像并成功标记细胞表面抗原^[67], QD凭借其独特的光物理性能和纳米尺寸, 在生物传感与疾病诊断等领域展现出广阔前景。然而, 未经修饰的QD在生物应用中存在局限^[68]: 一方面, 其表面常带有疏水基团或电荷, 导致生物相容性较差, 易发生聚集或被免疫系统快速清除; 另一方面, 其缺乏主动靶向性和高效的细胞穿透能力, 限制了其在细胞内成像与药物递送中的应用。

CPPs或HPs修饰是提升量子点生物功能的重要策略。Lee等^[69]研究表明, L6 CPPs可通过非共价作用与QD形成稳定的复合物, 并通过内吞途径高效进入A549细胞, 可显著增强其细胞渗透效率。其中CPPs与QD的连接常借助交联剂, 如1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐可以与QD表面的伯胺形成稳定的酰胺键, 实现CPPs和QD的定向结合^[70]。

Ghafary等^[71]设计了由MiRGD肽与石墨烯量子点(graphene quantum dots, GQD) 组成的新型纳米载体, 用于协同递送DOX和Cur治疗乳腺癌。研究表明, MiRGD肽修饰可促进GQD载体被αv整合素过表达的细胞内化, 实现主动靶向; 同时, GQD的荧光特性可实现药物的有效示踪, 提升了递送系统的可控性与可视化。

3.4　CPPs及HPs修饰聚合物

由合成或天然高分子材料构建的聚合物纳米载体, 尤其是胶束和纳米粒(nanoparticles, NPs), 因其结构可塑性强、药物负载范围广, 可递送小分子、蛋白质及核酸药物而备受关注^[72]。然而, 尽管经过PEG修饰可以延长其体内循环时间, 但其靶向穿透性仍有待优化^[73]。CPPs或HPs的修饰为解决这一问题提供了有效策略, 通过增强载体的细胞穿透能力与组织靶向性, 显著提升药物递送效率。

3.4.1　CPPs及HPs修饰胶束

胶束是由两亲性聚合物在水中自组装形成的纳米载体, 其粒径通常为10~100 nm。凭借其独特的“核-壳”结构, 胶束的疏水内核可包载脂溶性药物, 而亲水外壳则有助于减少血浆蛋白吸附, 降低单核吞噬系统的识别与清除, 从而提高胶体稳定性并延长体内循环时间^[74]。此外, 胶束可利用实体瘤的EPR效应实现被动靶向富集^[75]。然而, 未经修饰的胶束缺乏高效的细胞穿透能力与主动靶向性, 导致药物难以有效进入靶细胞, 限制了其在病灶部位的最大化疗效。

为克服普通胶束的穿透与靶向局限, CPPs与HPs的修饰为其提供了关键解决方案。Wan等^[76]构建了GALA肽与CREKA肽共修饰聚乙烯亚胺纳米粒(GC-NPs), 用于递送siRNA治疗三阴性乳腺癌。根据靶向评价结果表明, GC-NPs的肿瘤靶向指数为0.107, 比未经修饰的NPs提升了2.37倍。这表明GALA肽和CREKA肽修饰的NPs通过增强细胞摄取实现药物有效递送, 显著增强肿瘤靶向性并降低不良反应。

Zeng等^[77]构建了由线性TT1肽(linTT1, THPs) 修饰负载多柔比星的谷胱甘肽响应聚合物胶束, 用于乳腺癌治疗。研究结果表明, 经TT1肽修饰的胶束肿瘤荧光信号高于未经修饰组, 且肿瘤抑制率为70.7%, 证实TT1肽的修饰明显增强了胶束对4T1肿瘤的靶向性。

3.4.2　CPPs及HPs修饰纳米粒

3.4.2.1　CPPs及HPs修饰介孔二氧化硅纳米粒

介孔二氧化硅纳米粒(mesoporous silica nanoparticles, MSN) 因其高比表面积、良好的生物相容性、可调的孔径与孔道结构、易于表面功能化及优异的载药和缓释性能, 成为一种极具前景的药物递送载体^[78]。然而, 其临床应用存在两大关键挑战: 一是孔径过小, 限制了大分子核酸等药物的负载与运输^[79]; 二是未经修饰的MSNs在体内递送过程中面临生物屏障穿透效率低、靶向性不足的挑战。

为解决以上问题, 除调节孔径外, 核心策略是通过物理吸附或化学偶联方式将CPPs或HPs修饰于MSNs表面。Shadmani等^[80]构建了TAT肽修饰负载甲氨蝶呤的MSN。研究显示, 经TAT修饰组中大脑AUC_0-2h较未经修饰组提高了约11.1倍, 表明经TAT肽修饰能高效介导MSN跨越血脑屏障。

You等^[81]设计CHP肽功能化负载达格列净的MSN治疗心力衰竭, 结果显示, 经CHP肽修饰组左心室的缩短分数值为37.6%, 其疗效优于未经修饰组, 表明CHP肽能增强MSN递送药物至心脏病变部位, 促进心功能恢复。

3.4.2.2　CPPs及HPs修饰金纳米粒

金纳米粒(goldnanoparticles, GNPs) 是一类具有独特光学性质、良好生物相容性且能渗透深层组织的纳米载体。其表面易通过金-硫醇键实现抗体、多肽或药物进行高效偶联, 因此在诊疗一体化平台构建中显示出广阔前景^[70]。然而, 未经修饰的GNPs缺乏主动靶向能力且细胞内化效率有限, 这严重限制了其在体内的应用效果。因此, 采用CPPs或HPs对GNPs进行表面修饰, 是提升其递送效率和靶向性的重要策略。

在增强细胞摄取方面, 多种CPPs已通过金-硫醇键或共价偶联等方式成功修饰于GNPs表面, 借助其穿膜活性促进GNPs的跨膜转运效率。Khamehchian等^[82]研究了源于毛罗甘辛动物毒素的CPPs——MCaUF19肽修饰GNPs的细胞摄取特性。通过暗场成像和原子吸收光谱法的评估, 结果显示, 经MCaUF19肽修饰的GNPs组摄取量均高于未经修饰的GNPs组, 证实了该CPPs能增强GNPs细胞内化。

在实现主动靶向修饰方面, HPs发挥着关键作用。Wu等^[83]构建了cNGR环肽修饰的金纳米颗粒探针。CT成像结果表明, 同一时间点, 经cNGR肽修饰的CNP在肿瘤部位累积产生的CT信号值高于未经修饰GNPs-PEG, 证实cNGR肽可实现GNPs对肿瘤血管的特异性靶向, 提升其在肿瘤成像中的信号值与诊断效果。

4　CPPs及HPs修饰纳米载体突破生理屏障

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生理屏障是制约药物在体内有效递送的主要障碍。这些由特殊组织结构构成的精密防御体系, 根据其分布与功能, 可分为血脑屏障、眼部屏障、黏膜屏障及皮肤屏障四大类^[1]。各类屏障的结构特征与药物递送存在显著差异。CPPs与HPs分别具备“非特异性高效穿透”与“特异性靶向富集”的独特特性, 通过对纳米载体的独立修饰, 可针对性解决上述屏障的递送难题。

4.1　突破血脑屏障

血脑屏障(blood-brain barrier, BBB) 是由脑毛细血管内皮细胞紧密连接构成的特殊界面, 它既是保护中枢神经系统免受血液中有害物质侵袭的物理与代谢屏障, 也是维持脑内环境稳定的关键结构。然而, 该屏障也阻止了大多数大分子物质和约98%的小分子药物进入中枢神经系统^[3]。这严重阻碍了阿尔茨海默病、脑胶质瘤等中枢神经系统疾病的药物治疗。尽管纳米递药系统为BBB穿透带来了新希望, 但未经修饰的纳米载体自身穿透紧密连接内皮细胞的效率有限, 难以满足临床治疗需求^[84]。CPPs或HPs的修饰为解决这一难题提供了针对性方案。

CPPs修饰的纳米载体可借助其高效穿膜能力直接穿越内皮细胞层, 显著提升BBB穿透效率。Yuan等^[85]采用R8肽修饰多柔比星脂质体, 通过U87-MG细胞考察其内化效果。结果显示, 经R8肽修饰脂质体的摄取量是未经修饰脂质体的8.6倍, 证实了CPPs在促进载体跨BBB转运方面的显著作用。然而, 需要注意的是, CPPs的穿膜作用普遍缺乏细胞选择性, 其在靶向病变脑组织的同时, 也会对正常脑组织产生非特异性的相互作用, 潜在地带来不可预测的毒性风险^[86]。因此, 如何平衡CPPs的高效穿透性与其细胞非选择性, 是其在脑部递送应用中亟需解决的关键问题。

HPs修饰则通过识别BBB上的特异性表达受体实现主动靶向转运。Zhou等^[35]构建了RVG29肽修饰负载利福平(rifampicin, RIF) 的纳米颗粒, 用于阿尔茨海默病的诊疗。体内荧光成像显示, 经RVG29肽修饰组的荧光信号强度比未经修饰组增强了近3倍, 表明RVG29肽介导的主动靶向机制能引导纳米载体跨越BBB, 显著提升药物在脑组织的富集与生物利用度。

4.2　突破眼部屏障

眼部屏障系统主要包括前屏障与后眼部屏障, 在保护眼球内部结构的同时, 也严重限制了药物的有效递送, 具体表现为眼表滞留时间短、角膜渗透性差及生物利用度低^[87]。因此, 突破眼部屏障以实现高效药物递送, 是提高眼部疾病治疗效果的关键。纳米载体技术通过延长滞留、改善溶解性及实现靶向递送等机制, 为克服眼部屏障提供了新途径^[88]。近年来, 采用CPPs或HPs对纳米载体进行功能化修饰, 已成为提高药物角膜渗透性和生物利用度的有效策略。

CPPs主要通过膜穿透能力来改善药物在眼部递送效率。Suwannoi等^[89]利用TAT修饰负载阿昔洛韦的白蛋白纳米粒, 用于病毒性角膜炎的治疗。该研究比较了连接法与包覆法两种TAT肽修饰策略。结果显示, 经包覆的TAT-NPs细胞毒性低, 且其具有最高的角膜渗透性。表明经TAT肽修饰能促进纳米载体跨越眼部屏障, 提高药物递送效率。

HPs则通过识别眼部病变部位特异性表达的受体, 延长药物在眼部的滞留时间并提高靶组织富集度, 从而显著提升药物的生物利用度。Wang等^[90]设计了经RGD修饰共载光花菁和索拉非尼的脂质体治疗脉络膜新生血管(choroidal neovascularization, CNV)。研究结果显示, 经RGD肽修饰的CNV抑制效果最强, 表明RGD肽可特异性结合CNV区域中高表达整合素, 提高药物在病变部位富集。

4.3　突破黏膜屏障

黏膜屏障是覆盖于鼻腔、呼吸道、胃肠道及生殖道等腔道组织表面的动态防御体系, 其核心结构为“黏液层-上皮细胞层”双层屏障。黏液层富含黏蛋白, 可通过黏附、酶解等机制阻挡外来物质入侵; 上皮细胞层则通过紧密连接形成物理屏障, 进一步限制药物渗透^[91]。尽管黏膜给药可避开肝脏首关代谢, 提高药物生物利用度, 但由于这种双重屏障结构, 使多数药物的递送效率较低, 难以有效穿透达到治疗浓度。目前, CPPs或HPs已成为用于纳米药物表面修饰的重要策略, 它们通过不同机制显著提升纳米载体的黏膜穿透效率。

CPPs凭借其强穿透能力, 可同时突破黏液层和上皮细胞层的阻碍, 显著提升纳米载体的黏膜递送效率; 部分HPs也可通过与黏膜细胞表面受体的结合, 辅助纳米载体克服双重屏障。以下是它们在不同黏膜屏障中的应用。

4.3.1　鼻腔黏膜屏障

鼻腔黏膜是药物吸收的重要部位, 但黏液清除机制和上皮屏障严重限制了药物的吸收效率。Kanazawa等^[92]采用TAT肽修饰PEG和聚ε-己内酯嵌段共聚物胶束递送喜树碱与siRNA。经鼻腔给药后, TAT肽通过鼻黏膜上皮的直接渗透作用促进胶束进入脑脊液, 成功将药物递送至大鼠神经胶质瘤部位, 肿瘤抑制率达68%, 且无明显全身毒性, 为脑内疾病的局部靶向递送提供了高效策略。

4.3.2　呼吸道黏膜屏障

呼吸道黏膜屏障由气道表面的黏液层与上皮细胞组成, 是肺部给药的主要障碍。Gupta等^[93]构建了CAR肽修饰负载法舒地尔的聚合物胶束用于肺部给药。研究结果表明, 与未经修饰的胶束相比, CAR肽使细胞摄取量提升了约1.7倍, 药物在肺部的半衰期延长了约5倍, 显著提高了药物在肺部的疗效和滞留时间。

4.3.3　胃肠道黏膜

胃肠道黏膜屏障是口服给药面临的主要挑战, 其通过胃酸降解、黏液黏附及上皮阻隔等机制严重限制了药物的吸收。Tan等^[94]构建了Penetratin肽和PEG共修饰的MSN, 形成可穿透黏液的静电粒子复合物。研究结果表明, 在黏液环境中, 该纳米粒的细胞摄取、胞吐和跨细胞渗透分别提高8.45、1.62和5.09倍。Sheng等^[95]采用低分子质量鱼精蛋白(low molecular weight protamine, LMWP) 肽修饰聚乳酸-羟基乙酸共聚物纳米粒, 用于口服递送胰岛素。实验证明经LMWP肽修饰地增强了NPs在胃肠道黏膜的黏附和渗透性作用, 从而提高了胰岛素的口服吸收效率。

4.3.4　阴道黏膜屏障

阴道黏膜屏障由黏液层和上皮细胞紧密连接构成, 严重限制了药物在阴道内的滞留和渗透。Lv等^[96]设计了经TAT肽修饰的多西他赛纳米晶体, 用于治疗宫颈癌。结果表明, 与未经修饰的纳米晶体相比, 修饰后的纳米晶体延长了药物在阴道内滞留时间, 增强了其黏膜穿透能力, 对小鼠原位宫颈癌生长有更强的抑制作用。

4.4　突破皮肤屏障

经皮给药作为一种非侵入性方式, 具有延长药物作用时间、减轻全身毒副作用及提高患者依从性等优势。然而, 药物透皮过程中受到皮肤屏障——尤其是角质细胞与脂质有序排列构成的致密角质层, 极大地限制了药物的渗透, 使其难以达到有效治疗浓度。为克服这一屏障, 萜烯类、亚砜类、月桂氮酮类及吡咯烷酮类等化学促渗剂被开发并应用, 然而, 这些传统促渗剂常伴随生物相容性低或皮肤刺激性强等问题^[97]。相比之下, 基于CPPs及HPs的修饰策略因其高生物相容性与特异性强等优势, 成为增强药物皮肤穿透与靶向递送的研究热点。

CPPs主要通过增强纳米载体对角质层的穿透能力提高药物的经皮递送效率。Park等^[98]采用TAT肽修饰基于聚合物胶束的片状可变形纳米载体, 体内透皮给药实验结果表明, 与未经修饰的纳米载体相比, 经TAT肽修饰的细胞摄取量提高了约30倍, 透皮递送效率提升了60%以上。表明经TAT肽修饰能促进纳米载体有效穿透角质层。

HPs通过识别皮肤病变区域中特异性高表达的受体, 实现纳米载体的主动靶向, 从而增强药物在病灶部位的富集并降低对正常组织的影响。Yin等^[99]合成环状RGD肽偶联金纳米团簇(RGD-GNCs) 用于治疗黑色素瘤。结果显示, 与未经修饰的GNCs相比, RGD-GNCs与A375细胞孵育0.5 h, 显示出更强烈的荧光, 表明GNCs表面偶联的环状RGD肽通过受体介导的内吞作用促进了A375细胞的摄取。

5　结语与展望

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近年来, 纳米载体凭借其独特的理化性质(如纳米尺寸效应) 和易于功能化修饰的特点, 已成为新型药物递送系统的研究热点。然而, 与小分子药物不同, 纳米载体固有的物理化学属性使其难以自由穿透多重生理屏障。其细胞摄取主要依赖效率较低的内吞途径, 导致其递送效率低和靶向性不足等问题^[100]。因此, 通过CPPs或HPs对纳米载体进行表面功能化修饰, 是提升其屏障穿透能力和组织/细胞特异性的关键策略之一。具体而言, CPPs能够高效介导纳米载体跨越细胞膜屏障, 显著提升胞内药物浓度, 增强载体在体循环中的稳定性; 而HPs则能通过特异性识别肿瘤细胞或微环境中的标志物, 实现主动靶向与高效内化, 从而显著提升药物在靶部位的富集。

尽管CPPs或HPs功能化的纳米载体在克服各种生理屏障方面展现出巨大潜力, 但其迈向临床转化和产业化仍面临严峻挑战, 这些挑战主要集中在作用机制不明确、体内稳定性、免疫原性、靶向精准性及大规模生产可行性5个关键维度。

首先, 作用机制不明确是当前研究的难点。多肽的跨膜转运与靶向性是其电荷、疏水性、二级结构与复杂生物环境多元动态相互作用的结果, 并非由单一因素决定。因此, 未来的研究应侧重于计算机模拟、活体成像技术及粒子追踪技术等技术层面, 深入阐明CPPs与HPs修饰纳米载体的内在转运途径及与生物体系的相互作用机制。

其次, 体内稳定性是影响多肽修饰制剂生物利用度的主要障碍。多数多肽易被血浆和组织中的蛋白酶快速降解, 导致半衰期短, 生物利用度低。为克服这一难题, 研究者们主要从化学修饰策略^[101], 如主链环化、引入非天然氨基酸及末端修饰改变其被蛋白酶识别的特性; 物理包载策略, 如将其修饰在纳米载体表面或者包载于内部, 纳米载体作为物理屏障保护其在递送中被降解。

再者, 尽管CPPs/HPs通常被认为具有低免疫原性, 但其长期给药的潜在免疫风险不容忽视。长期或重复给药可能引发T细胞依赖的免疫反应, 导致药物抗体的产生, 甚至引发过敏反应。此外, 免疫原性的高低与多肽的序列、修饰方式、给药途径和个体差异密切相关。因此, 在药物开发早期, 应利用计算机辅助预测工具筛选低免疫原性序列, 并在临床前研究中系统评估重复给药的细胞免疫反应, 以确保治疗安全。

此外, 定向递送的准确性是决定治疗成功的关键因素。HPs的靶向性依赖于与表面特异性受体的结合, 然而某些受体在病变部位过度表达的同时, 在某些正常器官中也存在一定程度的表达, 易导致脱靶现象^[102]。研究者们可主要通过研发条件激活型前肽或设计多靶向肽等策略来降低这一风险。未来的临床开发中, 必须进行全面的临床前安全性评价, 重点关注与靶点生理功能相关的器官, 以保障临床用药安全。

最后, 在产业转化方面, 大规模制备肽-纳米载体仍面临挑战。核心问题在于如何将实验室中复杂的多肽合成、纯化及与纳米载体偶联工艺, 放大为稳定、经济且可控的工业化生产。未来的研究应侧重于开发高效、环保的多肽合成工艺, 降低制备成本; 建立完善的质量检测系统, 确保药品批次间质量均一性与安全性; 并解决纳米载体在长期存储中的理化稳定性问题。

综上所述, 推动CPPs/HPs功能化的纳米载体的临床转化需要系统性地克服上述多重挑战。但随着研究的不断深入, 通过持续优化策略和技术创新, CPPs与HPs功能化的纳米载体有望成为突破多重生理屏障的下一代智能递药系统, 推动靶向治疗在临床中的广泛应用。

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2026年第61卷第5期

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doi: 10.16438/j.0513-4870.2025-1069

接收时间：2025-09-08
首发时间：2026-09-21
出版时间：2026-05-12

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收稿日期：2025-09-08
修回日期：2025-11-20

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江西中医药大学, 现代中药制剂教育部重点实验室, 江西南昌 330004

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陈颖翀, Tel: 86-791-87118658, E-mail: yc_chen1020@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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