# Programmed Cell Death via Type IV Photodynamic Therapy Using Internalized Two-Photon Activated Molecular Nanomachines

## TL;DR

This paper introduces a new type of photodynamic therapy that uses light-activated nanomachines to induce programmed cell death in cancer cells without damaging surrounding tissues.

## Contribution

The novel use of light-activated molecular nanomachines to switch between necrotic and programmed cell death modes in cancer treatment.

## Key findings

- PEG or TPP+ modified nanomachines can cross cell membranes and localize at mitochondria.
- Activation from within cells induces programmed cell death without membrane rupture.
- A single technology can switch between necrotic and non-necrotic cell death modes.

## Abstract

Direct photodynamic therapy (PDT) is a growing research
area currently
being explored as an alternative treatment for various cancers. 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.