Nanobowl-confined hydrophobic phase disperses ER-targeted AIE photosensitizers as dynamic aggregates for precision photodynamic therapy.

Overcoming premature activation of aggregation-induced emission photosensitizers (AIE-PSs) before they reach the tumor is critical for the broad clinical application of photodynamic therapy (PDT). Here, we report a bowl-shaped nanoplatform as a universal AIE delivery vessel, together with a new endoplasmic reticulum (ER)-targeting AIE PS (TSQE), for precision PDT. A hollow polydopamine (PDA) nanobowl was fabricated to confine oleic acid (OA) molecules within its cavity, forming a localized hydrophobic phase that attracts and disperses TSQE molecules into dynamic aggregates, thereby enabling efficient delivery while avoiding premature activation. The TSQE-OA mixture responds to pH stimuli in the tumor microenvironment, resulting in specific TSQE accumulation in the ER of tumor cells. Additionally, upconversion nanoparticles (UCNPs) co-loaded in the nanobowl enable deep-tissue activation of the TSQE molecules using 980 nm light, triggering potent apoptosis and ferroptosis via ER stress and lipid peroxidation (LPO). The therapeutic effect is further amplified by manganese deposited on the PDA shell, which catalyzes reactive oxygen species (ROS) generation in combination with the PDA's photothermal effect under 808 nm irradiation. In vitro and in vivo studies demonstrate superior and specific anti-tumor efficacy. Our nanobowl-based delivery platform and the TSQE represent a dual-level strategy for improving PDT precision.