Cascade-responsive size/charge bidirectional-tunable nanodelivery penetrates pancreatic tumor barriers

Yiqi Shi; Jinghan Liao; Cuiyun Zhang; Qi Wu; Shanshan Hu; Ting Yang; Jihong Liu; Zhirong Zhu; Wei-Hong Zhu; Qi Wang

doi:10.1039/D4SC04782F

Cascade-responsive size/charge bidirectional-tunable nanodelivery penetrates pancreatic tumor barriers†

Yiqi Shi,^a Jinghan Liao,^b Cuiyun Zhang,^a Qi Wu,^a Shanshan Hu,^a Ting Yang,^c Jihong Liu,^a Zhirong Zhu,^a Wei-Hong Zhu

^a and Qi Wang

*^a

Author affiliations

* Corresponding authors

^a Shanghai Key Laboratory of Functional Materials Chemistry, Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China
E-mail: wangqi@ecust.edu.cn

^b State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 2200/25 Xietu Road, Shanghai, China

^c Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab for Biomaterials, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

Abstract

The pancreatic tumor microenvironment presents multiple obstacles for polymer-based drug delivery systems, limiting tumor penetration and treatment efficacy. Here, we engineer a hyaluronidase/reactive oxygen species cascade-responsive size/charge bidirectional-tunable nanodelivery (btND, G/R@TKP/HA) for co-delivery of gemcitabine and KRAS siRNA, capable of navigating through tumor barriers and augmenting anticancer efficiency. When penetrating the tumor stroma barrier, the hyaluronic acid shell of the nanodelivery undergoes degradation by hyaluronidase in an extracellular matrix, triggering size tuning from large to small and charge tuning from negative to positive, thereby facilitating deeper penetration and cellular internalization. After endocytosis, the nanodelivery protonizes in the endo/lysosome, prompting rapid endo/lysosomal escape, effectively overcoming the lysosome barrier. Intracellular ROS further disrupt the nanodelivery, inducing its size tuning again from small to large and a positive charge decrease for high tumor retention and controlled drug release. The btND shows remarkable antitumor activity in pancreatic cancer mouse models, highlighting the efficacy of this approach in penetrating tumor barriers and enhancing anticancer outcomes.

Chemical Science

Cascade-responsive size/charge bidirectional-tunable nanodelivery penetrates pancreatic tumor barriers†

Abstract

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Cascade-responsive size/charge bidirectional-tunable nanodelivery penetrates pancreatic tumor barriers

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