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Compared to traditional, indirect PDT, which exploits the reaction of oxygen with the photosensitizer (PS) to damage specially targeted cells, direct PDT utilizes the PS itself to disrupt the target cell, meaning no reactive oxygen species (ROS) are generated. The activation of Type IV technologies specifically induces a structural change within the photosensitizer, resulting in the activation of its therapeutic effect. In contrast to traditional invasive surgeries, chemotherapy, or ROS-based methods, direct methods of PDT pose significantly less damaging off-target effects. Here, we propose an exciting extension of our prior reported, near-infrared light-activated, molecular nanomachines (MNMs), previously shown to promote cell-specific necrosis via disruption of cellular membranes. We show that the modification of MNMs with polyethylene glycol (PEG), or triphenol phosphonium (TPP+) containing functional groups, allows for homeostatic crossing of the phospholipid bilayer and localization at the mitochondrial membrane. By subsequent activation of the rotor from within the targeted cells, we present the ability to eliminate cells without triggering necrotic cell death, instead inducing an additional mechanism of programmed cell death (PCD), while maintaining the integrity of the cellular membrane, thus enacting a significantly cleaner, more therapeutically favorable mode of inducing cell death. A significant development is in the use of light-activated molecular machines for cancer treatments, with a single MNM-based technology being able to access both necrotic and non-necrotic modes of cell elimination by simply switching the excitation procedure.<\/jats:p>","DOI":"10.1021\/acsabm.5c01318","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T15:46:21Z","timestamp":1760370381000},"page":"9982-9992","source":"Crossref","is-referenced-by-count":1,"title":["Programmed Cell Death\nvia Type IV Photodynamic Therapy\nUsing Internalized Two-Photon Activated Molecular Nanomachines"],"prefix":"10.1021","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2623-2225","authenticated-orcid":true,"given":"Thomas. 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