A Mitochondria-Targeted Photosensitizer for Combined Pyroptosis and Apoptosis with NIR-II Fluorescence/Photoacoustic Imaging-Guided Phototherapy.

Overcoming tumor apoptosis resistance is a major challenge in enhancing cancer therapy. Pyroptosis, a lytic form of programmed cell death (PCD) involving inflammasomes, Gasdermin family proteins, and cysteine proteases, offers potential in cancer treatment. While photodynamic therapy (PDT) can induce pyroptosis by generating reactive oxygen species (ROS) through the activation of photosensitizers (PSs), many PSs lack specific subcellular targets and are limited to the first near-infrared window, potentially reducing treatment effectiveness. Therefore, developing effective, deep-penetrating, organelle-targeted pyroptosis-mediated phototherapy is essential for cancer treatment strategies. Here, we synthesized four molecules with varying benzene ring numbers in thiopyrylium structures to preliminarily explore their photodynamic properties. The near-infrared-II (NIR-II) PS Z1, with a higher benzene ring count, exhibited superior ROS generation and mitochondria-targeting abilities, and a large Stokes shift. Through nano-precipitation method, Z1 nanoparticles (NPs) also demonstrated high ROS generation (especially type-I ROS) upon 808 nm laser irradiation, leading to efficient mitochondria dysfunction and combined pyroptosis and apoptosis. Moreover, they exhibited exceptional tumor-targeting ability via NIR-II fluorescence imaging (NIR-II FI) and photoacoustic imaging (PAI). Furthermore, Z1 NPs-mediated phototherapy effectively inhibited tumor growth with minimal adverse effects. Our findings offer a promising strategy for cancer therapy, warranting further preclinical investigations in PDT.

Size Modulation of Conjugated Polymer Nanoparticles for Improved NIR-II Fluorescence Imaging and Photothermal Therapy.

Near-infrared-II fluorescence imaging (NIR-II FI) has become a powerful imaging technique for disease diagnosis owing to its superiorities, including high sensitivity, high spatial resolution, deep imaging depth, and low background interference. Despite the widespread application of conjugated polymer nanoparticles (CPNs) for NIR-II FI, most of the developed CPNs have quite low NIR-II fluorescence quantum yields based on the energy gap law, which makes high-sensitivity and high-resolution imaging toward deep lesions still a huge challenge. This work proposes a nanoengineering strategy to modulate the size of CPNs aimed at optimizing their NIR-II fluorescence performance for improved NIR-II phototheranostics. By adjusting the initial concentration of the synthesized conjugated polymer, a series of CPNs with different particle sizes are successfully prepared via a nanoprecipitation approach. Results show that the NIR-II fluorescence brightness of CPNs gradually amplifies with decreasing particle size, and the optimal CPNs, NP0.2, demonstrate up to a 2.05-fold fluorescence enhancement compared with the counterpart nanoparticles. With the merits of reliable biocompatibility, high photostability, and efficient light-heat conversion, the optimal NP0.2 has been successfully employed for NIR-II FI-guided photothermal therapy both in vitro and in vivo. Our work highlights an effective strategy of nanoengineering to improve the NIR-II performance of CPNs, advancing the development of NIR-II FI in life sciences.

Oligomerization Strategy of D-A-Type Conjugated Molecules for Improved NIR-II Fluorescence Imaging.

Fluorescence imaging (FI) in the second near-infrared (NIR-II) window has emerged as a promising imaging method for cancer diagnosis because of its superior properties such as deep penetration depth and high signal-to-background ratio. Despite the superiorities of organic conjugated nanomaterials for NIR-II FI, the issues of low fluorescence quantum yield, weak metabolic capability, undefined molecular structure for conjugated polymers, weak light-harvesting ability, short emission wavelength, and high synthetic complexity for conjugated small molecules still remain to be concerned. We herein propose an oligomerization strategy by facilely adjusting the oligomerization time to balance the advantages and disadvantages between conjugated polymers and small molecules, obtaining the candidate (CO1, oligomerization time: 1 min) with the optimal NIR-II optical performance. Then the CO1 is further prepared into water-dispersed nanoparticles (CON1) via a nanoprecipitation approach. By virtue of the suitable size, excellent NIR-II optical properties, low toxicity, and strong cell-labeling ability, the CON1 is successfully employed for in vivo NIR-II imaging, permitting the real-time visualization of blood vascular system and tumors with high sensitivity and resolution. This work thus not only provides a personalized organic conjugated nano-agent for NIR-II FI, but also highlights the molecular strategy for the development of organic conjugated systems with optimal performance for bio-imaging.