Dual-Stimuli-Driven Calcium Nanomachines for NO-Induced Immunogenic Cell Death

Abstract Tumor blood vascular endothelial cells targeting has emerged as a powerful strategy to enhance the accumulation and penetration of nanomedicines. However, the complex tumor microenvironment, especially the newly discovered breast cancer blood vascular basement membrane, can severely trap accumulated nanomedicines and compromise therapeutic efficacy. In this study, a γ-glutamyl transpeptidase (GGT)-targeting calcium nanomachine is designed and fabricated through decoration of GGT-targeting polysarcosine and encapsulation of nitric oxide (NO) precursors. Upon NIR laser irradiation, these calcium nanomachines can efficiently release NO on demand. By integration of the GGT-targeting and NIR-triggered NO release, these nanomachines can actively target the 4T1 tumor, deeply penetrate into tumor region, and are efficiently internalized by 4T1 cells. Robust tumor cell apoptosis and immunogenic cell death (ICD) can be achieved as well as efficient immune activation. Meanwhile, these calcium nanomachines can also greatly inhibit 4T1 lung metastasis and demonstrate significant efficacy against large tumors. This work offers a great opportunity for the facile design and construction of precision nanomedicines.