Surface-Functionalized Polymeric siRNA Nanoparticles for Tunable Targeting and Intracellular Delivery to Hematologic Cancer Cells

Eunji Kwak; Taehyung Kim; Kyungjik Yang; Young Min Kim; Hwa Seung Han; Kyung Hoon Park; Ki Young Choi; Young Hoon Roh

doi:10.1021/acs.biomac.1c01497

Surface-Functionalized Polymeric siRNA Nanoparticles for Tunable Targeting and Intracellular Delivery to Hematologic Cancer Cells

Eunji Kwak, Taehyung Kim, Kyungjik Yang, Young Min Kim, Hwa Seung Han, Kyung Hoon Park, Ki Young Choi, Young Hoon Roh

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

2 Citations (Scopus)

Abstract

To date, the application of RNA therapeutics to hematologic malignancies has been challenging owing to the resistance of blood cancer cells against conventional transfection methods. Herein, triple-targeting moiety-functionalized polymeric small interfering RNA (siRNA) nanoparticles were systematically developed for efficient targeted delivery of RNA therapeutics to hematologic cancer cells. Polymeric siRNAs were synthesized using rolling circle transcription and were surface-functionalized with three types of targeting moieties─a natural ligand and two additional combinations of cell-specific antibodies─for tunable targetability. As a proof of concept, the optimization of the hyaluronic acid/antibody conjugation ratio was performed for selective intracellular delivery to various non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Raji, Ramos, and Toledo cells) via receptor-mediated endocytosis. The engineered nanoparticles showed almost 10-fold enhanced NHL-specific intracellular delivery and induced significant in vitro anticancer effects. This multitargeted nanoparticle platform may effectively support the intracellular delivery of polymeric siRNA sequences, and thus promote therapeutic effects in hematopoietic malignancies.

Original language	English
Pages (from-to)	2255-2263
Number of pages	9
Journal	Biomacromolecules
Volume	23
Issue number	6
DOIs	https://doi.org/10.1021/acs.biomac.1c01497
Publication status	Published - 2022 Jun 13

Bibliographical note

Funding Information:
This work was supported by the Basic Science Research Program (no. 2018R1D1A1A02085552, no. 2020M3F7A1094089, no. 2021R1A6A3A13044758, and no. 2021R1I1A1A01060428) through the National Research Foundation of Korea (NRF) funded by the Korean Government and in part by the Brain Korea 21 (BK21) FOUR program. K.Y. was supported by the NRF-2017-Global Ph.D. Fellowship program.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

All Science Journal Classification (ASJC) codes

Bioengineering
Biomaterials
Polymers and Plastics
Materials Chemistry

UN SDGs

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

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10.1021/acs.biomac.1c01497

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title = "Surface-Functionalized Polymeric siRNA Nanoparticles for Tunable Targeting and Intracellular Delivery to Hematologic Cancer Cells",

abstract = "To date, the application of RNA therapeutics to hematologic malignancies has been challenging owing to the resistance of blood cancer cells against conventional transfection methods. Herein, triple-targeting moiety-functionalized polymeric small interfering RNA (siRNA) nanoparticles were systematically developed for efficient targeted delivery of RNA therapeutics to hematologic cancer cells. Polymeric siRNAs were synthesized using rolling circle transcription and were surface-functionalized with three types of targeting moieties─a natural ligand and two additional combinations of cell-specific antibodies─for tunable targetability. As a proof of concept, the optimization of the hyaluronic acid/antibody conjugation ratio was performed for selective intracellular delivery to various non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Raji, Ramos, and Toledo cells) via receptor-mediated endocytosis. The engineered nanoparticles showed almost 10-fold enhanced NHL-specific intracellular delivery and induced significant in vitro anticancer effects. This multitargeted nanoparticle platform may effectively support the intracellular delivery of polymeric siRNA sequences, and thus promote therapeutic effects in hematopoietic malignancies.",

author = "Eunji Kwak and Taehyung Kim and Kyungjik Yang and Kim, {Young Min} and Han, {Hwa Seung} and Park, {Kyung Hoon} and Choi, {Ki Young} and Roh, {Young Hoon}",

note = "Funding Information: This work was supported by the Basic Science Research Program (no. 2018R1D1A1A02085552, no. 2020M3F7A1094089, no. 2021R1A6A3A13044758, and no. 2021R1I1A1A01060428) through the National Research Foundation of Korea (NRF) funded by the Korean Government and in part by the Brain Korea 21 (BK21) FOUR program. K.Y. was supported by the NRF-2017-Global Ph.D. Fellowship program. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

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AU - Kwak, Eunji

AU - Kim, Taehyung

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AU - Kim, Young Min

AU - Han, Hwa Seung

AU - Park, Kyung Hoon

AU - Choi, Ki Young

AU - Roh, Young Hoon

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PY - 2022/6/13

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N2 - To date, the application of RNA therapeutics to hematologic malignancies has been challenging owing to the resistance of blood cancer cells against conventional transfection methods. Herein, triple-targeting moiety-functionalized polymeric small interfering RNA (siRNA) nanoparticles were systematically developed for efficient targeted delivery of RNA therapeutics to hematologic cancer cells. Polymeric siRNAs were synthesized using rolling circle transcription and were surface-functionalized with three types of targeting moieties─a natural ligand and two additional combinations of cell-specific antibodies─for tunable targetability. As a proof of concept, the optimization of the hyaluronic acid/antibody conjugation ratio was performed for selective intracellular delivery to various non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Raji, Ramos, and Toledo cells) via receptor-mediated endocytosis. The engineered nanoparticles showed almost 10-fold enhanced NHL-specific intracellular delivery and induced significant in vitro anticancer effects. This multitargeted nanoparticle platform may effectively support the intracellular delivery of polymeric siRNA sequences, and thus promote therapeutic effects in hematopoietic malignancies.

AB - To date, the application of RNA therapeutics to hematologic malignancies has been challenging owing to the resistance of blood cancer cells against conventional transfection methods. Herein, triple-targeting moiety-functionalized polymeric small interfering RNA (siRNA) nanoparticles were systematically developed for efficient targeted delivery of RNA therapeutics to hematologic cancer cells. Polymeric siRNAs were synthesized using rolling circle transcription and were surface-functionalized with three types of targeting moieties─a natural ligand and two additional combinations of cell-specific antibodies─for tunable targetability. As a proof of concept, the optimization of the hyaluronic acid/antibody conjugation ratio was performed for selective intracellular delivery to various non-Hodgkin's lymphoma (NHL) cell lines (Daudi, Raji, Ramos, and Toledo cells) via receptor-mediated endocytosis. The engineered nanoparticles showed almost 10-fold enhanced NHL-specific intracellular delivery and induced significant in vitro anticancer effects. This multitargeted nanoparticle platform may effectively support the intracellular delivery of polymeric siRNA sequences, and thus promote therapeutic effects in hematopoietic malignancies.

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Surface-Functionalized Polymeric siRNA Nanoparticles for Tunable Targeting and Intracellular Delivery to Hematologic Cancer Cells

Abstract

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