Rational development of gemcitabine-based nanoplatform for targeting SERPINB9/Granzyme B axis to overcome chemo-immune-resistance

Haozhe Huang, Yiqing Mu, Yixian Huang, Beihong Ji, Yifei Wang, Chien-Yu Chen, Yuang Chen, Zhangyi Luo, Sihan Li, Ziqian Zhang, Luxuan Wang, James F. Conway, Da Yang, Junmei Wang (), Jingjing Sun () and Song Li ()
Additional contact information
Haozhe Huang: University of Pittsburgh
Yiqing Mu: University of Pittsburgh
Yixian Huang: University of Pittsburgh
Beihong Ji: University of Pittsburgh
Yifei Wang: University of Pittsburgh
Chien-Yu Chen: University of Pittsburgh
Yuang Chen: University of Pittsburgh
Zhangyi Luo: University of Pittsburgh
Sihan Li: University of Pittsburgh
Ziqian Zhang: University of Pittsburgh
Luxuan Wang: University of Pittsburgh
James F. Conway: University of Pittsburgh
Da Yang: University of Pittsburgh
Junmei Wang: University of Pittsburgh
Jingjing Sun: University of Pittsburgh
Song Li: University of Pittsburgh

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract SERPINB9, an endogenous inhibitor of granzyme B (GzmB), has emerged as a critical factor in the resistance to immunotherapy by protecting cancer cells from GzmB-induced cytotoxicity. However, its role in chemosensitivity remains unknown. In this study, we show that gemcitabine (GEM) treatment upregulates SERPINB9 through transcription factor ATF-3. Interestingly, GEM also induces the expression of GzmB and knockout or knockdown of SERPINB9 results in enhanced response of tumor cells to GEM, suggesting a role of GzmB/SERPINB9 axis in regulating chemosensitivity. To facilitate the therapeutic translation of these findings, we engineer POEM nanocarrier (consisting of lipid-derivatized polylysine (PEG-PLL-Oleic acid, PPO), and GEM-conjugated polylysine (PEG-PLL-OA-GEM, PPOGEM), PPO/PPOGEM (POEM)) that is highly effective in codelivery of built-in GEM and loaded SERPINB9 short interfering RNA (siSPB9). GEM conjugation introduces an additional mechanism of carrier/siRNA interaction in addition to charge-mediated interaction and enables efficient i.v. delivery at lower N/P ratios. Here, we show that co-delivery of GEM and siSPB9 significantly improves antitumor efficacy and remodels the tumor immune microenvironment in pancreatic cancer models, supporting a promising therapeutic strategy.

Date: 2025
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DOI: 10.1038/s41467-025-59490-y

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