ABSTRACT Type‐I photodynamic therapy (PDT) is highly effective against hypoxic tumors, with its efficacy further enhanced by near‐infrared‐II (NIR‐II, 1000–1700 nm) excitation, which offers deeper tissue penetration than conventional NIR‐I (700–1000 nm). However, most reported organic NIR‐II photosensitizers (PSs) are only NIR‐II emissive but remain NIR‐I‐excited. NIR‐II‐excited type‐I PSs are rare and generally limited by low ROS yields, often requiring high‐power irradiation with photothermal co‐treatment to achieve meaningful therapeutic outcomes. Thus, rationally designing efficient organic type‐I PSs directly activated by NIR‐II light remains a challenge. Herein, we report a general strategy for designing efficient NIR‐II‐excited organic Type‐I PSs (PNT‐PFT NPs) based on linked donor‐acceptor through‐space charge transfer (CT) for PDT of hypoxic solid tumors. The through‐space CT based on linked donor‐acceptor pairs redshifts and amplifies the NIR‐II absorption of the PNT–PFT NPs. Additionally, the donor‐acceptor energy alignment facilitates directional flow of electrons, increasing free‐electron yield for O 2 ‐to‐ROS conversion. As a result, PNT–PFT NPs efficiently generated ROS and achieved 89.3% tumor inhibition in 4T1 models under low‐power 1064 nm irradiation. This study not only offers a general guideline for tailoring NIR‐II‐excited Type‐I PSs via through‐space CT in linked donor‐acceptor pairs but also provides mechanistic insights into Type‐I PS design.
Tang et al. (Fri,) studied this question.