Light- and X-ray-Activated Liposomes for Controlled Gene Editing and Drug Delivery.

Novel BODIPY-Loaded Liposomes Enhance Cellular Uptake and PDT Efficacy in 2D and 3D Models

Background: Photodynamic therapy (PDT) is a cancer treatment that combines a photosensitizer (PS), light, and oxygen to generate reactive oxygen species (ROS), leading to tumor cell death. PDT efficacy depends largely on PS accumulation within tumors, prompting the development of third-generation PSs and nanotechnology-based delivery systems. Among these, BODIPYs (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) are promising PSs due to their favorable photophysical properties, while liposomes improve drug delivery, cellular uptake, and sustained release profiles. This study describes the synthesis of two novel BODIPY derivatives differing in the position of a methyl ester group on the meso-phenyl ring, their incorporation into liposomes, and evaluation of PDT efficacy. Methods: Cellular uptake of BODIPY-loaded liposomes, intracellular ROS generation, apoptosis, necrosis, and lipid peroxidation were assessed by flow cytometry in colorectal and ovarian cancer cell lines. The antitumor activity of the liposomal formulations was further evaluated in both 2D and 3D models using MTT and clonogenic assays. The involvement of ferroptosis and necroptosis in PDT-induced cell death was also investigated. Results: Liposomal formulations significantly enhanced cellular uptake compared with free compounds. Following light activation, both formulations induced potent antitumor effects through multiple cell death mechanisms, including canonical and non-canonical pathways, and maintained strong efficacy in 3D tumor spheroids. Conclusions: Liposome-encapsulated BODIPYs represent promising PDT agents by improving cellular uptake and eliciting robust antitumor activity through complementary cell death mechanisms. Furthermore, the methyl ester substituent on the meso-phenyl ring provides a versatile platform for future conjugation with targeting ligands, supporting the development of third-generation, tumor-targeted photosensitizers and warranting further preclinical investigation.

Insights Into Natural Photosensitizer‐Based Nanotherapeutics in Photodynamic Therapy of Cancer

Photodynamic therapy (PDT) is a minimally invasive cancer treatment that uses photosensitizers (PSs), light, and oxygen to generate cytotoxic reactive oxygen species. Natural product‐derived PSs, including alkaloids, flavonoids, polyphenols, curcuminoids, perylenequinones, phycocyanin, and anthraquinones, offer advantages such as biocompatibility and low toxicity but are limited by poor solubility, stability, and targeting. Nanotherapeutic systems such as organic, inorganic, and carbon‐based nanoparticles, nanogels, hydrogels, lipid carriers, and nanoemulsions address these limitations by enhancing stability, tumor accumulation, and controlled release. These platforms also enable multifunctional approaches, including imaging‐guided PDT, combination therapies, and stimuli‐responsive activation. This review highlights mechanisms, recent advances, and translational challenges of natural PS‐based nanotherapeutics across multiple cancers, emphasizing strategies to improve delivery, selectivity, and therapeutic outcomes for next‐generation PDT.

A Chloroplast-Inspired Theranostic Nanoplatform for Self-Sustaining Oxygen-Elevating Photodynamic Therapy and Glutathione-Triggered Carbon-Centered Radical Synergistic Therapy.

Achieving precise drug delivery to the tumor site can minimize systemic side effects caused by off-target effects. As a therapy that depends on oxygen content, photodynamic therapy (PDT) is significantly constrained by the hypoxic nature of the tumor microenvironment (TME). Compared with the limited efficacy of single PDT, the combination of multiple treatment modalities can achieve synergistic enhancement and superior therapeutic outcomes. Since carbon radical therapy does not rely on oxygen as a reactive substrate, it is mechanistically complementary to oxygen-dependent PDT. In this work, we report a novel strategy for developing a theranostic nanoplatform for long-lasting PDT activated by 1530 nm laser irradiation and glutathione (GSH)-triggered carbon-centered radical synergistic therapy that responds specifically to the TME. This theranostic nanoplatform (UCNPs@WOR:AF@CDC, UWAC) comprises three components: GSH-responsive engineered vesicles (CDC), functionalized metal-organic frameworks (WOR) encapsulating lanthanide upconversion nanoparticles (UCNPs@WOR, UW), and carbon radical prodrugs (ART-Fe, AF). Lanthanide-based upconversion nanoparticles (UCNPs) could upconvert 1530 nm light to 1390 nm for attenuation-minimized second near-infrared (NIR-II) fluorescence imaging and to visible light that serves as the light source for photocatalysis for water oxidation. The 1530 nm light-activated generation of reactive oxygen species (ROS), enhanced by UW-mediated hydrolytic oxygen evolution, works in synergy with the GSH-triggered release of the carbon radical prodrug (AF) to achieve long-lasting therapeutic outcomes. Importantly, it could achieve tumor-specific drug release, triggered by the degradation of the engineered vesicles in response to elevated GSH levels. This work develops a novel theranostic nanoplatform, which could achieve GSH-activated drug delivery, deep-tissue penetration, and a long-lasting therapeutic effect.

New strategies to enhance photodynamic therapy for solid tumors

A Triple‐Stage Precision Carbon Dot Nanogel With Cascade Activation for Spatiotemporally Controlled Chemo–Photodynamic Therapy

Conventional chemotherapy is limited by poor cellular uptake and low tumor selectivity, often requiring high systemic doses that increase off‑target toxicity. Here we report a triple‑stage precision nanogel (CDX@nano) in which carbon dots (CDs) serve as organelle‑targeted delivery vehicles. The nanogel is surface‐functionalized with indomethacin for tumor‑specific homing and encapsulates CDs conjugated with doxorubicin (DOX) via glutathione‐cleavable disulfide linkages. Upon near‐infrared irradiation, the CDs generate singlet oxygen, triggering nanogel disassembly, and rapid drug release. The liberated CDs accumulate in mitochondria, elevating reactive oxygen species and disrupting redox homeostasis, while DOX translocates to the nucleus to induce DNA damage. This cascade‐activated, dual‐compartment assault integrates photodynamic and chemotherapeutic modalities. In vitro, CDX@nano reduced tumor cell viability to 8.5% upon irradiation, showing approximately 4.5‑fold greater potency than non‐targeted controls. In vivo, it achieved over 85% tumor growth inhibition with minimal systemic toxicity. This triple‐stage platform offers a promising strategy to overcome key barriers in cancer therapy.

A lipid droplet-targeted AIE photosensitizer for efficient multi-type ROS generation and breast cancer photodynamic therapy.

Photodynamic therapy (PDT) is a promising non-invasive strategy for breast cancer, yet its clinical translation is hindered by fluorescence quenching, insufficient reactive oxygen species (ROS) generation and poor tumor targeting. Herein, a novel lipid droplet-targeted aggregation-induced emission (AIE) photosensitizer CTC was designed and synthesized. CTC has a large Stokes shift of 150 nm to avoid self-absorption and exhibits typical AIE properties in aqueous environments. Under white light irradiation, it efficiently generates three cytotoxic ROS (1O2, ·OH, O2•-), with a high colocalization coefficient of 0.95 with lipid droplets in 4 T1 cells. CTC shows excellent biocompatibility in the dark and potent phototoxicity under illumination. In vivo, CTC combined with light significantly inhibits 4 T1 tumor growth without systemic toxicity. Density functional theory calculations elucidate its multi-type ROS generation mechanism, providing a novel candidate and new insight for safe and efficient breast cancer PDT.