Jiannan Ren,1,* Menglin Song,1,* Dongbing Ding,1,* Tianyun Lan,2 Yiquan Li,1 Rongpu Liang,1 Shengxin Huang,1 Guangchun Jiang,1 Jiarong You,1 Jianming Yang,1 Chi Chen,1 Weiyi Luan,3 Bekhzod Abdullaev,4 He Huang,1 Yang Zhao,1 Bo Wei1 

1Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, People’s Republic of China; 2Central Laboratory, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, People’s Republic of China; 3Shaoguan University, Shaoguan, 512005, People’s Republic of China; 4Research Department of Biotechnology, New Uzbekistan University, Tashkent, Uzbekistan

*These authors contributed equally to this work

Correspondence: Bo Wei, Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, People’s Republic of China, Tel +86 20 85252228, Email weibo3@mail.sysu.edu.cn

Introduction: Oxaliplatin (OXA) and 5-fluorouracil (5-Fu) are standard chemotherapy agents used to treat advanced gastric cancer (GC). However, their clinical efficacy is often limited by systemic toxicity, poor tumor selectivity, and suboptimal therapeutic outcomes when administered as monotherapy. These limitations underscore the need for innovative approaches to improve chemotherapy sensitivity and treatment efficacy.
Methods: We developed a glucose-responsive, RGD peptide-functionalized biporous silica nanocarrier (R-BSN). This system integrates hollow glucose oxidase (hGOx)-modified micelles onto hollow mesoporous silica nanoparticles functionalized with RGD peptides, enabling targeted, sustained drug release and inducing a starvation effect in tumor cells.
Results: The glucose-triggered biporous release strategy significantly prolongs the drug release profile, ensuring sustained chemotherapy delivery while simultaneously depleting intratumoral glucose to enhance therapeutic efficacy. This strategy not only increases chemotherapy potency but also exacerbates oxidative stress in tumor cells, leading to the induction of immunogenic cell death (ICD). Furthermore, R-BSN exhibits robust anti-tumor activity in both subcutaneous tumor models and peritoneal metastasis models, supporting its potential for multi-pathway tumor eradication.
Conclusion: The glucose-triggered biporous silica nanocarrier offers a promising strategy to enhance chemotherapy outcomes in advanced gastric cancer, integrating sustained drug release, starvation therapy, and amplification of oxidative stress. This approach holds significant potential for clinical translation in gastric cancer treatment.

Keywords: biporous silica nanocarrier, glucose-responsive, sequential sustained chemotherapy, starvation therapy, advanced gastric cancer