Cinnamaldehyde-Based Self-Assembled Nanodrugs with GSH Depletion for Antitumor through Photodynamic Therapy Enhanced Ferroptosis and Immunotherapy

Utilizing nanotechnology to deliver multiple anticancer drugs holds the potential to enhance the anticancer effect. However, most drug carriers have limitations such as their own toxicity and low drug loading rate. Besides, depleting the excessive glutathione (GSH) in tumor cells not only induces ferroptosis in cancer cells but also has the potential to enhance photodynamic therapy. Inspired by previous work, hydroxyl groups were introduced into the ferroptosis inducer cinnamaldehyde to enhance its hydrogen bond interaction with the photosensitizer chlorins e6, thereby constructing stable self-assembled nanodrugs in solution and naming them TC. The prepared nanodrugs possess high drug loading capacity and acidic-responsive release properties, enabling efficient accumulation in tumor tissues. The TC not only consumes GSH through 3, 4, 5-trihydroxycinnamic aldehyde and down-regulate glutathione peroxidase 4, but also generates reactive oxygen species under irradiation, thereby increasing the level of lipid peroxidation and causing cancer cell apoptosis as well as ferroptosis. Additionally, the immunogenic cell death caused by combined therapy releases tumor-associated antigens, enhances antitumor immune responses, and inhibits tumor growth and metastasis in vivo and in vitro experiments, with no obvious toxicity. This study offers a unique molecular assembly modification strategy for the construction of self-assembled nanoplatforms to advance the field of carrier-free nanodrug.