Nuclear‐Targeted Nanostrategy Regulates Spatiotemporal Communication for Dual Antitumor Immunity

Abstract 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 are 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 is developed to establish positive spatiotemporal communication, further activating dual antitumor immunity, namely innate and adaptative immunity. The mSiO 2 ‐Ion@Ce6‐NLS nanoparticles (NPs) are designed, whose surface is modified by ionic liquid silicon (Ion) and nuclear localization signal peptide (NLS: PKKKRKV), and their pores are loaded with the photosensitizer hydrogen chloride e6 (Ce6). Ion‐modified NPs enhance intratumoral enrichment, and NLS‐modified NPs exhibit nuclear‐targeted characteristics to achieve nuclear‐targeted photodynamic therapy (nPDT). mSiO 2 ‐Ion@Ce6‐NLS with nPDT facilitate the release of damaged double‐stranded DNA from tumor cells to activate macrophages via stimulator of interferon gene signaling and induce 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 strengthens positive communication to reshape the dual antitumor immune microenvironment, further inducing long‐term immune memory, and eventually inhibiting tumor growth and recurrence.