Development of a Modular Ribonucleoprotein Complex as a General Strategy to Deliver RNAi Therapeutics

Nok Yin Tam; Xiaoqi Wang; Grace Chung Yan Chan; Wai Po Kong; Wai Yin Chau; Xiuqiong Fu; Kwok Yin Wong; Hong Lok Lung; Zhi Ling Yu; Wei Shen Aik

doi:10.1002/adhm.202503281

Development of a Modular Ribonucleoprotein Complex as a General Strategy to Deliver RNAi Therapeutics

Nok Yin Tam
, Xiaoqi Wang
, Grace Chung Yan Chan
, Wai Po Kong
, Wai Yin Chau
, Xiuqiong Fu
, Kwok Yin Wong
, Hong Lok Lung
, Zhi Ling Yu^*
, Wei Shen Aik^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

Abstract

RNAi therapeutics can potentially address undruggable diseases. However, their full potential is stymied by delivery challenges. An siRNA delivery platform by remodeling the human U4 small nuclear ribonucleoprotein complex (snRNP) is developed. This remodeled protein-siRNA complex (SmiRNP) serves as a biocompatible, modular, and customizable platform for attaching desired functional modules to overcome delivery hurdles. Here, it is demonstrated that the SmiRNP complex, by using siRNA against KRAS as a proof of principle, can deliver the siRNA into cells and protect it from nuclease degradation, allowing the siRNA to knockdown KRAS mRNA and protein levels, reduce cancer cell viability, and suppress tumor growth in vivo. This general strategy allows many more modular combinations and would enable the delivery of a wide spectrum of RNAi therapeutics.

Original language	English
Article number	e03281
Number of pages	13
Journal	Advanced Healthcare Materials
Volume	14
Issue number	25
Early online date	23 Jul 2025
DOIs	https://doi.org/10.1002/adhm.202503281
Publication status	Published - 26 Sept 2025

User-Defined Keywords

KRAS
protein-based delivery agent
ribonucleoprotein complex
RNAi therapeutics
siRNA delivery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/adhm.202503281

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title = "Development of a Modular Ribonucleoprotein Complex as a General Strategy to Deliver RNAi Therapeutics",

abstract = "RNAi therapeutics can potentially address undruggable diseases. However, their full potential is stymied by delivery challenges. An siRNA delivery platform by remodeling the human U4 small nuclear ribonucleoprotein complex (snRNP) is developed. This remodeled protein-siRNA complex (SmiRNP) serves as a biocompatible, modular, and customizable platform for attaching desired functional modules to overcome delivery hurdles. Here, it is demonstrated that the SmiRNP complex, by using siRNA against KRAS as a proof of principle, can deliver the siRNA into cells and protect it from nuclease degradation, allowing the siRNA to knockdown KRAS mRNA and protein levels, reduce cancer cell viability, and suppress tumor growth in vivo. This general strategy allows many more modular combinations and would enable the delivery of a wide spectrum of RNAi therapeutics.",

keywords = "KRAS, protein-based delivery agent, ribonucleoprotein complex, RNAi therapeutics, siRNA delivery",

author = "Tam, \{Nok Yin\} and Xiaoqi Wang and Chan, \{Grace Chung Yan\} and Kong, \{Wai Po\} and Chau, \{Wai Yin\} and Xiuqiong Fu and Wong, \{Kwok Yin\} and Lung, \{Hong Lok\} and Yu, \{Zhi Ling\} and Aik, \{Wei Shen\}",

note = "N.Y.T. and X.W. contributed equally to this work. We thank the Faculty of Science and the Department of Chemistry of Hong Kong Baptist University for funding. We thank Liang Tong for providing plasmids for expression of SmD3/SmB1-95 and SmG/SmE/SmF, and for commenting on the manuscript. We also gratefully acknowledge the support from the University Research Facility in Life Sciences of the Hong Kong Polytechnic University for the electron microscopy studies. Publisher Copyright: {\textcopyright} 2025 The Author(s). Advanced Healthcare Materials published by Wiley-VCH GmbH.",

year = "2025",

month = sep,

day = "26",

doi = "10.1002/adhm.202503281",

language = "English",

volume = "14",

journal = "Advanced Healthcare Materials",

issn = "2192-2640",

publisher = "John Wiley \& Sons Ltd",

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}

TY - JOUR

T1 - Development of a Modular Ribonucleoprotein Complex as a General Strategy to Deliver RNAi Therapeutics

AU - Tam, Nok Yin

AU - Wang, Xiaoqi

AU - Chan, Grace Chung Yan

AU - Kong, Wai Po

AU - Chau, Wai Yin

AU - Fu, Xiuqiong

AU - Wong, Kwok Yin

AU - Lung, Hong Lok

AU - Yu, Zhi Ling

AU - Aik, Wei Shen

N1 - N.Y.T. and X.W. contributed equally to this work. We thank the Faculty of Science and the Department of Chemistry of Hong Kong Baptist University for funding. We thank Liang Tong for providing plasmids for expression of SmD3/SmB1-95 and SmG/SmE/SmF, and for commenting on the manuscript. We also gratefully acknowledge the support from the University Research Facility in Life Sciences of the Hong Kong Polytechnic University for the electron microscopy studies. Publisher Copyright: © 2025 The Author(s). Advanced Healthcare Materials published by Wiley-VCH GmbH.

PY - 2025/9/26

Y1 - 2025/9/26

N2 - RNAi therapeutics can potentially address undruggable diseases. However, their full potential is stymied by delivery challenges. An siRNA delivery platform by remodeling the human U4 small nuclear ribonucleoprotein complex (snRNP) is developed. This remodeled protein-siRNA complex (SmiRNP) serves as a biocompatible, modular, and customizable platform for attaching desired functional modules to overcome delivery hurdles. Here, it is demonstrated that the SmiRNP complex, by using siRNA against KRAS as a proof of principle, can deliver the siRNA into cells and protect it from nuclease degradation, allowing the siRNA to knockdown KRAS mRNA and protein levels, reduce cancer cell viability, and suppress tumor growth in vivo. This general strategy allows many more modular combinations and would enable the delivery of a wide spectrum of RNAi therapeutics.

AB - RNAi therapeutics can potentially address undruggable diseases. However, their full potential is stymied by delivery challenges. An siRNA delivery platform by remodeling the human U4 small nuclear ribonucleoprotein complex (snRNP) is developed. This remodeled protein-siRNA complex (SmiRNP) serves as a biocompatible, modular, and customizable platform for attaching desired functional modules to overcome delivery hurdles. Here, it is demonstrated that the SmiRNP complex, by using siRNA against KRAS as a proof of principle, can deliver the siRNA into cells and protect it from nuclease degradation, allowing the siRNA to knockdown KRAS mRNA and protein levels, reduce cancer cell viability, and suppress tumor growth in vivo. This general strategy allows many more modular combinations and would enable the delivery of a wide spectrum of RNAi therapeutics.

KW - KRAS

KW - protein-based delivery agent

KW - ribonucleoprotein complex

KW - RNAi therapeutics

KW - siRNA delivery

UR - https://www.scopus.com/pages/publications/105011825936

U2 - 10.1002/adhm.202503281

DO - 10.1002/adhm.202503281

M3 - Journal article

AN - SCOPUS:105011825936

SN - 2192-2640

VL - 14

JO - Advanced Healthcare Materials

JF - Advanced Healthcare Materials

IS - 25

M1 - e03281

ER -

Development of a Modular Ribonucleoprotein Complex as a General Strategy to Deliver RNAi Therapeutics

Abstract

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