Causal factors for osteoarthritis risk revealed by mendelian randomization analysis.

Osteoarthritis (OA), a prevalent chronic disease among the elderly, presents a complex pathogenesis and currently lacks effective treatment. Traditional observational studies are time-consuming, labor-intensive, susceptible to confounding factors, and cannot establish causal relationships. Mendelian randomization (MR) analysis, leveraging genetic variation to assess causal associations between exposures and outcomes, offers a cost-effective and efficient alternative. Over the past decade, large-scale genome-wide association studies have identified numerous genetic variants linked to OA risk factors, facilitating MR study design. In this review, we systematically identified 52 MR studies meeting specific criteria and evaluated their quality, exploring the impact of lifestyle, nutrition, comorbidities, circulating metabolites, plasma proteins, and other health factors on OA risk. We discuss the results and potential mechanisms of MR findings, addressing conflicting evidence based on existing literature and our prior research. With the ongoing expansion of genome-wide association data, we anticipate MR's role in future OA studies to broaden, particularly in drug development research using targeted MR approaches. We thus aim for this paper to offer valuable insights for researchers and clinicians in related fields.

NIR-responsive nanoplatform for pre/intraoperative image-guided carcinoma surgery and photothermal ablation of residual tumor tissue.

Local recurrence is common among patients with advanced cancer who have undergone surgery. Here, we developed a new surgical treatment for cancer based on a nanoparticle that loaded a near-infrared dye (IR780 iodide) and perfluorooctyl bromide into liposomes (NP-IR780). In an orthotopic breast cancer mouse model, NP-IR780 was demonstrated to have excellent tumor-targeting ability due to the selective tumor accumulation of IR780 iodide and the enhanced permeation and retention effect of the nanoparticle. With the excellent targeting ability, concurrent computed tomography and photoacoustic imaging were achieved for preoperative planning. In particular, NP-IR780 could serve as a tumor indicator for near-infrared fluorescence image-guided precise resection of lesions during surgery. Importantly, residual tumors could be ablated through intraoperative photothermal therapy without obvious recurrence. This work provides a theranostic strategy that significantly improved the survival of mice through pre/intraoperative image-guided tumor resection and subsequent photothermal therapy of residual lesions.

A preliminary study of photoacoustic/ultrasound dual-mode imaging in melanoma using MAGE-targeted gold nanoparticles.

Nanoprobes are small enough to circulate within the vasculature and can reach tumour tissues through the endothelial gap, providing a new strategy for accurate tumour monitoring and imaging-guided antitumour therapy at the molecular level. Both photoacoustic and ultrasonic imaging are noninvasive tools for cancer detection via the application of nanoprobes. In this study, a polymeric multifunctional nanoparticle probe loaded with gold nanorods (Au-NRs) and liquid perfluorocarbon (perfluorinated hexane/PFH) and conjugated to a monoclonal antibody (MAGE-1 antibody) to melanoma-associated antigens (MAGE) targeting melanoma was successfully prepared by the double emulsion and carbodiimide methods as a targeted photoacoustic/ultrasound dual-mode imaging contrast agent (MAGE-Au-PFH-NPs). Cell-targeting experiments in vitro showed large amounts of MAGE-Au-PFH-NPs surrounding B16 melanoma cells in the targeted group. The photoacoustic signal in the targeted group was significantly increased, and the duration was longer than that in the untargeted group in vivo. The photoacoustic signal of the nanoprobes was enhanced with increased Au-NR concentration in the photoacoustic experiment in vitro. The enhanced signal was observed by ultrasound after 808-nm laser irradiation. A cytotoxicity and biocompatibility test showed that MAGE-Au-PFH-NPs exhibited good biological safety. The MAGE-Au-PFH-NPs can be used as a photoacoustic/ultrasound dual-mode contrast agent to lay the foundation for a promising new approach for the noninvasive targeting, monitoring and treatment of tumours.

Mitochondria-Targeted and Ultrasound-Activated Nanodroplets for Enhanced Deep-Penetration Sonodynamic Cancer Therapy.

Sonodynamic therapy (SDT), a promising alternative for cancer therapy, utilizes a sonosensitizer combined with ultrasound (US) irradiation to damage tumor cells/tissues for therapeutic purposes. The ability of sonosensitizers to specifically accumulate in tumor cells/tissues could greatly influence their therapeutic efficiency. In this work, we report the use of US-activated sonosensitizer (IR780)-based nanodroplets (IR780-NDs) for SDT, which provide numerous benefits for killing cancer cells compared with traditional methods. For instance, IR780-NDs showed effective surface-to-core diffusion both in vitro and in vivo. In the presence of US, the acoustic droplet vaporization (ADV) effect significantly assisted the conveyance of IR780-NDs from the circulatory system to tumor regions, and the acoustic wave force also increased the penetration depth within tumor tissues. Furthermore, IR780-NDs possesses mitochondrial targeting capabilities, which improves the precision and accuracy of SDT delivery. During the in vitro assessment, the overproduction of reactive oxygen species (ROS) was observed following mitochondrial targeting, which rendered cancer cells more susceptible to ROS-induced apoptosis. Additionally, IR780-ND is a suitable candidate for photoacoustic and fluorescence imaging and can also enhance US imaging because of the ADV-generated bubbles, which provides the potential for SDT guidance and monitoring. Therefore, with combined modalities, IR780-NDs can be a promising theranostics nanoplatform for cancer therapy.

IR780-loaded folate-targeted nanoparticles for near-infrared fluorescence image-guided surgery and photothermal therapy in ovarian cancer.

Background and purpose: Surgery is regarded as the gold standard for patients with advanced ovarian cancer. However, complete surgical removal of tumors remains extremely challenging; fewer than 40% of patients are cured. Here, we developed a new modality of theranostics for ovarian cancer based on a near-infrared light-triggered nanoparticle. Methods: Nanoparticles loading IR780 iodide on base of folate modified liposomes were prepared and used for theranostics of ovarian cancer. Tumor targeting of FA-IR780-NP was evaluated in vitro and in an ovarian xenograft tumor model. A fluorescence stereomicroscope was applied to evaluate the tumor recognition of FA-IR780-NP during surgery. FA-IR780-NP mediated photothermal therapy effect was compared with other treatments in vivo. Results: FA-IR780-NP was demonstrated to specifically accumulate in tumors. IR780 iodide selectively accumulated in tumors; the enhanced permeability and retention effect of the nanoparticles and the active targeting of folate contributed to the excellent tumor targeting of FA-IR780-NP. With the aid of tumor targeting, FA-IR780-NP could be used as an indicator for the real-time delineation of tumor margins during surgery. Furthermore, photothermal therapy mediated by FA-IR780-NP effectively eradicated ovarian cancer tumors compared with other groups. Conclusion: In this study, we present a potential, effective approach for ovarian cancer treatment through near-infrared fluorescence image-guided resection and photothermal therapy to eliminate malignant tissue.

Photothermal therapy mediated by phase-transformation nanoparticles facilitates delivery of anti-PD1 antibody and synergizes with antitumor immunotherapy for melanoma.

Melanoma remains one of the most challenging malignant tumor related deaths worldwide and alternative approaches to efficiently treat melanoma are eagerly needed. Anti-PD1 antibody (aPD1) immunotherapy is the most significant and impactful therapy for melanoma by immune checkpoint inhibition and T cell stimulation to mediate tumor killing. But the clinical remission rate of aPD1 immunotherapy is limited in melanoma. Here we show a potent combination of aPD1 and photothermal therapy (PTT) by effective delivery of a multifunctional phase-transformation nanocarrier to melanoma tumor. We successfully synthesized multifunctional nanoparticles (NPs) encapsulated with aPD1, iron oxide and perfluoropentane (PFP) in lactic-co-glycolic acid (PLGA) shell modified with poly ethylene glycol (PEG) and Gly-Arg-Gly-Asp-Ser (GRGDS) peptides (GOP@aPD1). In vitro, GOP@aPD1 NPs were characterized for particle size and drug-loading efficiency. The NPs were also tested for photothermal property, optical droplet vaporization (ODV) capacity and the ability of aPD1 release profile. In vivo, GOP@aPD1 NPs were systemically administered to melanoma-bearing mice demonstrated no toxicity and accumulation at tumor site. When mediated with PTT, this synergistic treatment achieved enhanced antitumor efficacy, due to combination of the effective aPD1 release and increased CD8+ T cell infiltration in tumor site. In conclusion, GOP@aPD1 NPs combined with PTT could potentiate the efficacy of aPD1 not only by tumor-targeted delivery of aPD1 but also by activating the immune system in the tumor microenvironment, which is a highly effective approach to treat melanoma.

Mitochondria-Targeted Artificial "Nano-RBCs" for Amplified Synergistic Cancer Phototherapy by a Single NIR Irradiation.

Phototherapy has emerged as a novel therapeutic modality for cancer treatment, but its low therapeutic efficacy severely hinders further extensive clinical translation and application. This study reports amplifying the phototherapeutic efficacy by constructing a near-infrared (NIR)-responsive multifunctional nanoplatform for synergistic cancer phototherapy by a single NIR irradiation, which can concurrently achieve mitochondria-targeting phototherapy, synergistic photothermal therapy (PTT)/photodynamic therapy (PDT), self-sufficient oxygen-augmented PDT, and multiple-imaging guidance/monitoring. Perfluorooctyl bromide based nanoliposomes are constructed for oxygen delivery into tumors, performing the functions of red blood cells (RBCs) for oxygen delivery ("Nano-RBC" nanosystem), which can alleviate the tumor hypoxia and enhance the PDT efficacy. The mitochondria-targeting performance for enhanced and synergistic PDT/PTT is demonstrated as assisted by nanoliposomes. In particular, these "Nano-RBCs" can also act as the contrast agents for concurrent computed tomography, photoacoustic, and fluorescence multiple imaging, providing the potential imaging capability for phototherapeutic guidance and monitoring. This provides a novel strategy to achieve high therapeutic efficacy of phototherapy by the rational design of multifunctional nanoplatforms with the unique performances of mitochondria targeting, synergistic PDT/PTT by a single NIR irradiation (808 nm), self-sufficient oxygen-augmented PDT, and multiple-imaging guidance/monitoring.