Photodynamic therapy (PDT) employs a photosensitizer (PS), light exposure, and molecular oxygen to produce reactive oxygen species (ROSs), which can trigger apoptosis or necrosis and suppress cancer cell proliferation [1]. Conventional PSs primarily generate toxic singlet oxygen (1O2) through photochemical pathway. Nevertheless, the efficacy of this therapy is often limited by the hypoxic conditions within tumors due to poorly organized vascular structures [2]. Furthermore, the nonspecific nature of PSs complicates targeting tumor cells [3].

Hypoxia, typified by inadequate oxygen, is common in malignant tumors and correlates with cancer metastasis [4]. The deficit in oxygen compromises cancer treatment, leading to poor clinical results and prognosis [5]. The chaotic vasculature characteristic of tumors and the restricted penetration of PSs contribute to an oxygen shortage within tumor regions, significantly diminishing the therapeutic impact on hypoxic tumors.

Researchers are examining new methodologies to fortify PDT against low oxygen conditions. One strategy involves developing advanced PSs capable of generating ROSs in low-oxygen environments, offering a viable counter to the issues posed by tumor hypoxia. Additional endeavors include identifying methods to bolster oxygen supply in hypoxic tumors during PDT, such as hyperbaric oxygen therapy and deploying oxygen-bearing nanoparticles [6], [7].

Moreover, integrating PDT with other therapeutic strategies appears promising in overcoming hypoxia-related dilemmas. Implementing PDT in conjunction with ferroptosis optimizes anti-tumor efficacy in oxygen-deprived settings [8]. Through combining ferroptosis and PDT, two strategies cooperatively elicit synergetic antitumor effects. Cellular ferroptosis enhances the efficacy PDT by generating ROS through Fenton or Fenton-like reactions (Fe2+ + H2O2 → Fe3+ + (OH)− + •OH) that continuously produce oxygen In addition, PDT also drives ferroptosis by triggering non-enzymatic lipid peroxidation with generated ROS [9].

To tackle the problem of limited tumor-targeting proficiency, employing organelle-targeting photosensitizers allows for the precise delivery of PSs to specified organelles. ROSs generated by PSs have a narrow activity radius and are short-lived [10]. Targeting organelles rather than the cytoplasm enables greater damage, thereby heightening PDT efficacy [11]. This refinement not only betters drug delivery effectiveness but also guarantees optimal concentrations for cell apoptosis induction [12]. Directing PSs to organelles such as mitochondria, lysosomes, and the endoplasmic reticulum significantly bolsters PDT’s effectiveness [13], [14], [15].

Mitochondria are critical in maintaining cellular redox stability and are crucial in regulating oxidative stress [16], which is integral to cell survival. Disruption in redox balance is implicated in various pathological states associated with cell death [17]. Thus, mitochondria-specific PSs are recommended for improving PDT outcomes [18], [19]. Many strategies have been crafted for mitochondria-targeted PS delivery, leveraging compounds like triphenylphosphonium (TPP) and methylated qualinium recognized for their lipid affinity and positive charge, enhancing mitochondrial uptake [20], [21]. These strategies accentuate the tumor-targeting facility and efficacy in ROSs generation under low-oxygen circumstances. Moreover, cholesterol plays a crucial role in cellular membranes, predominantly within lipid bilayers [22]. It has been noted that cholesterol selectively interfaces with tumor cells through receptor-mediated endocytosis [23], with previous research indicating that cholesterol substituted silicon phthalocyanine significantly curbs cancer cell growth [24].

Ferroptosis, a distinct form of non-apoptotic cell death, is characterized by the accumulation of lipid ROS and dependency on iron [25]. It involves processes that govern metabolic pathways including the inhibition of the cystine/glutamate antiporter (System Xc-), inactivation of GPX4, glutathione depletion, and alterations in iron metabolism [26].

Mitochondria, an organelle with a high iron content, undergo significant structural and functional changes during ferroptosis, which affect cellular energy generation activities including the breakdown of fatty acids, the tricarboxylic acid cycle, and the electron transport chain—key elements shaping ferroptosis progression [27]. Nonetheless, studies linking PSs-induced ferroptosis via mitochondrial dysfunction remain scarce.

In this investigation, a unique asymmetric silicon phthalocyanine (Chol-SiPc-TPP) photosensitizer is introduced, featuring cholesterol and triphenylphosphonium moieties and boasting an efficient cellular uptake, targeted mitochondrial delivery, and dual potential for two-photon fluorescence imaging-guided PDT.

Additionally, both PDT and ferroptosis inherently produce ROS within the tumor microenvironment (TME), propelling the destruction of cancer cells. Significantly, ferroptosis instigates the Fenton reaction, yielding ample oxygen to mitigate hypoxia in the TME and bolster PDT’s efficiency. To capitalize on this combinatorial strategy, a novel nanoparticle, FECTPN, has been engineered by encapsulating Chol-SiPc-TPP and the ferroptosis inducer Erastin within Ferritin. This study investigates the potential of FECTPN in accurately localizing and inducing ferroptosis in mitochondria, thus achieving the synergistic development of PDT-ferroptosis anti-tumor therapy. Fig. 1.