Nuclear-Targeted Nanostrategy Regulates Spatiotemporal Communication for Dual Antitumor Immunity

Intercellular communication between tumor cells and immune cells regulates tumor progression, including positive communication with immune activation and negative communication with immune escape. An increasing number of methods have been employed to suppress the dominant negative communication in tumors, such as PD-L1/PD-1. However, how to effectively improve positive communication is still a challenge. In this study, a nuclear-targeted photodynamic nanostrategy was developed to establish positive spatiotemporal communication, further activating dual antitumor immunity, namely innate and adaptative immunity. The mSiO 2 -Ion@Ce6-NLS nanoparticles (NPs) were designed, whose surface was modified by ionic liquid silicon (Ion) and nuclear localization signal peptide NLS (PKKKRKV), and their pores were loaded with the photosensitizer hydrogen chloride e6 (Ce6). Ion-modified NPs enhanced intratumoral enrichment, and NLS-modified NPs exhibited nuclear-targeted characteristics to achieve nuclear-targeted photodynamic therapy (nPDT). mSiO 2 -Ion@Ce6-NLS with nPDT facilitated the release of damaged dsDNA from tumor cells to activate macrophages via STING signaling, and induced the immunogenic cell death of tumor cells to activate dendritic cells via “eat me” signals, ultimately leading to the recruitment of CD8 + T-cells. This therapy effectively strengthened positive communication to reshape the dual antitumor immune microenvironment, further inducing long-term immune memory, and eventually inhibiting tumor growth and recurrence. This article is protected by copyright. All rights reserved