Efficient chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle as “in situ” vaccine integrated tumor ICD and immunoagonist
Yunfei Han, Mingxia Jiang, Yanju Sun, Wenqiang Chen, Yanli Zhao, Xiuwen Guan, Weifen Zhang
Abstract
INTRODUCTION: Immunotherapy has unprecedentedly opened up a series of neoteric tactics for cancer treatment. As a burgeoning approach, chemo-immunotherapy has innovatively expanded the accomplishments of conventional chemotherapeutic agents for cancer governing. OBJECTIVES: An efficacious chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle (NP) integrated tumor immunogenic cell death (ICD) and immunoagonist was developed as a watertight "in situ" vaccine for cancer therapy through convenient intratumoral administration with minimized systemic toxicity. METHODS: Chemical-modified pH-sensitive cis-aconityl-doxorubicin (CAD) and immunoadjuvant unmethylated cytosine-phosphate-guanine (CpG) were co-packaged by polycationic polyethylenimine (PEI) though electrostatic-interaction to construct PEI/CpG/CAD NP. By intratumoral injection, this positively charged NP could be detained at tumor site and endocytosed by tumor cells effortlessly. Then, doxorubicin was released through cis-aconityl cleavage induced by endosomal-acidity and further triggered tumor ICD, the moribund tumor cells could release damage-associated molecular patterns (DAMPs) to recruit dendritic cells (DCs). Meanwhile, the entire tumor debris derived into diversified antigens and cooperated with immunostimulatory CpG to excite DC maturation and activated comprehensive antitumor immunity. RESULTS: Prominent tumor suppression was achieved in aggressive mouse melanoma tumor model, which verified the feasibility and effectiveness of this minimalist CAD/CpG-codelivered NP. CONCLUSION: This study has provided a convenient and promising paradigm for potent cancer chemo-immunotherapy.