In contrast to Type-II photodynamic therapy (PDT), Type-I PDT with less oxygen consumption has shown great potential against tumor hypoxia. However, there are limited strategies available for designing Type-I photosensitizers (PSs). Herein, we present a promising strategy for synthesizing Type-I PSs (TBC-1-TBC-4) using Tröger's base (TB) framework. The TB framework can promote intersystem crossing efficiency and create an electron-rich environment, making it the most likely site for electron transfer to O2 to generate Type-I ROS. As anticipated, TBC-1-TBC-4 demonstrates Type-I ROS generation capability and their impressive visible light-harvesting ability significantly enhances this capability. Among them, TBC-1 demonstrates outstanding biocompatibility and PDT efficiency in vitro under both normoxia and hypoxia. Furthermore, TBC-1 effectively inhibits tumor growth in vivo, with negligible side effects. This is attributed to TBC-1's efficient generation of Type-I ROS and endoplasmic reticulum targeting ability. This study thus offers useful insights into developing Type-I PSs.