Work

A Two‐Stage Strategy to Reprogram Cyanine Photosensitizers as Controllable‐Pyroptosis Inducers for Anticancer Phototherapy

Year: 2026

Type: article

Abstract: Pyroptosis, a lytic and inflammatory form of programmed cell death, provides a promising strategy for antitumor immunotherapy. However, controllable modulation of pyroptosis using phototherapeutic agents remains challenging. In this study, we report a two-stage molecular reprogramming method to rationally design cyanine photosensitizers with tunable pyroptosis-inducing activity. We first reprogram IR808 into a novel photosensitizer T808, by integrating a tetraphenylethylene unit with IR808, which consequently enhances excited - state features related to intersystem crossing (ISC) and reactive oxygen species (ROS) generation capability, accompanied by inducing pyroptosis under irradiation. In the second process, T808 is conjugated with poly(ethylene glycol) (PEG) chains of varying lengths (M.W. 550, 1000, and 2000 Da) to finely modulate the pyroptotic efficacy. The relationship of PEG chain length with pyroptosis-inducing activity is in the order of PT550 > T808 > PT1000 >> PT2000. Cellular and in vivo studies show that T808, PT550, and PT1000 treatments suppress tumor growth and induce pyroptosis with occurrence of immunogenic cell death (ICD). Even under a lower intratumoral injection dose (25 µM), T808 and PT550 therapies exhibit remarkable antitumor efficacy with measurable pyroptosis features. This work provides a new insight into reprogramming cyanine photosensitizers into pyroptosis-active molecules, and proposes possible structural association of PEGylated cyanines with the pyroptosis activity.

Source: Advanced Healthcare Materials

DOI: 10.1002/adhm.71952