Awakening Allies for Breaking Microenvironment Barriers: NIR‐II Guided Orthogonal Activation of Tumor‐Infiltrating Mast Cells for Efficient Nano‐Drug Delivery

Abstract

AbstractMast cells (MCs), powerful immune cells that heavily infiltrate cancer cells, play a crucial role in tumor formation. Activated MCs can release histamine and a family of proteases through degranulation effects, concurrently achieving endothelial junction weakening and stromal degradation of the tumor microenvironment, thereby clearing the obstacles for nano‐drug infiltration. To achieve precise activation of tumor‐infiltrating MCs, orthogonally excited rare earth nanoparticles (ORENP), with two channels, are introduced for the controllable stimulating drugs release wrapped in “photocut tape”. The ORENP can emit near‐infrared II (NIR‐II) for image tracing for tumor localization in Channel 1 (808/NIR‐II) and allows energy upconversion to emit ultraviolet (UV) light for releasing drugs for MCs stimulation in Channel 2 (980/UV). Finally, the combined use of chemical and cellular tools enables clinical nano‐drugs to achieve a significant increase in tumor infiltration, thereby enhancing the efficacy of nano‐chemotherapy.