Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease

Zhaohan Li; Jun Yang; Jianan Li; Shuxuan Zhao; Shaoping Jiang; Weimin Liu; Xinjian Li; Simeng Zhang; Haiyan Du; Junjun Ni; Yuanyu Huang; Hong Qing; Shaobo Ruan

doi:10.1186/s40035-025-00503-7

Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease

Zhaohan Li, Jun Yang, Jianan Li, Shuxuan Zhao, Shaoping Jiang, Weimin Liu, Xinjian Li, Simeng Zhang, Haiyan Du, Junjun Ni, Yuanyu Huang^*, Hong Qing^*, Shaobo Ruan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Background: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. Methods: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). Results: PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. Conclusions: This study provides a reliable delivery platform for gene therapies for AD.

Original language	English
Article number	41
Journal	Translational Neurodegeneration
Volume	14
Issue number	1
DOIs	http://doi.org/10.1186/s40035-025-00503-7
Publication status	Published - Dec 2025

Keywords

Alzheimer's disease
Aβ
BACE1
Blood–brain barrier
Microglia
Nanomedicine
Neuroinflammation
siRNA

Access to Document

10.1186/s40035-025-00503-7

Cite this

@article{9a5e95955ad54ea58942366fe9893f7f,

title = "Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease",

abstract = "Background: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. Methods: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). Results: PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. Conclusions: This study provides a reliable delivery platform for gene therapies for AD.",

keywords = "Alzheimer's disease, Aβ, BACE1, Blood–brain barrier, Microglia, Nanomedicine, Neuroinflammation, siRNA",

author = "Zhaohan Li and Jun Yang and Jianan Li and Shuxuan Zhao and Shaoping Jiang and Weimin Liu and Xinjian Li and Simeng Zhang and Haiyan Du and Junjun Ni and Yuanyu Huang and Hong Qing and Shaobo Ruan",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1186/s40035-025-00503-7",

language = "English",

volume = "14",

journal = "Translational Neurodegeneration",

issn = "2047-9158",

publisher = "BioMed Central Ltd.",

number = "1",

}

TY - JOUR

T1 - Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease

AU - Li, Zhaohan

AU - Yang, Jun

AU - Li, Jianan

AU - Zhao, Shuxuan

AU - Jiang, Shaoping

AU - Liu, Weimin

AU - Li, Xinjian

AU - Zhang, Simeng

AU - Du, Haiyan

AU - Ni, Junjun

AU - Huang, Yuanyu

AU - Qing, Hong

AU - Ruan, Shaobo

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/12

Y1 - 2025/12

N2 - Background: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. Methods: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). Results: PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. Conclusions: This study provides a reliable delivery platform for gene therapies for AD.

AB - Background: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. Methods: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). Results: PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. Conclusions: This study provides a reliable delivery platform for gene therapies for AD.

KW - Alzheimer's disease

KW - Aβ

KW - BACE1

KW - Blood–brain barrier

KW - Microglia

KW - Nanomedicine

KW - Neuroinflammation

KW - siRNA

UR - http://www.scopus.com/pages/publications/105013363616

U2 - 10.1186/s40035-025-00503-7

DO - 10.1186/s40035-025-00503-7

M3 - Article

AN - SCOPUS:105013363616

SN - 2047-9158

VL - 14

JO - Translational Neurodegeneration

JF - Translational Neurodegeneration

IS - 1

M1 - 41

ER -

Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this