Delivery of Biomimetic Liposomes via Meningeal Lymphatic Vessels Route for Targeted Therapy of Parkinson's Disease.

Targeted therapy of Parkinson's disease is an important challenge because of the blood-brain barrier limitation. Here, we propose a natural killer cell membrane biomimetic nanocomplex (named BLIPO-CUR) delivered via the meningeal lymphatic vessel (MLV) route to further the therapeutic efficacy of Parkinson's disease. The membrane incorporation enables BLIPO-CUR to target the damaged neurons, thus improving their therapeutic efficacy through clearing reactive oxygen species, suppressing the aggregation of α-synuclein, and inhibiting the spread of excess α-synuclein species. Compared with the conventional intravenous injection, this MLV administration can enhance the delivered efficiency of curcumin into the brain by ~20 folds. The MLV route administration of BLIPO-CUR enhances the treatment efficacy of Parkinson's disease in mouse models by improving their movement disorders and reversing neuron death. Our findings highlight the great potential of MLV route administration used as targeted delivery of drugs to the brain, holding a great promise for neurodegenerative disease therapy.

Miniature NIR-II Nanoprobes for Active-Targeted Phototheranostics of Brain Tumors.

Nanoprobes (NPs) in the second near-infrared biowindow (NIR-II, 1000-1700 nm) are developed and widely used in cancer phototheranostics. However, most NIR-II NPs exhibit low phototheranostic efficiency due to their tedious synthetic routes, large particle sizes (>20 nm), and lack of active targeting properties. Here, miniature NIR-II NPs, named HSA-ICG-iRGD, for active-targeted NIR-II phototheranostics of brain tumors are reported. The HSA-ICG-iRGD probes are designed based on hydrophobic interactions as well as hydrogen bonds between albumin and indocyanine green derivatives (ICG-iRGD) via molecular docking. The as-prepared NPs have a compact size of 10 nm and show tumor-targeting ability by specifically binding to αv ß3 integrin receptors which are highly expressed on the surface of brain tumor cells via iRGD peptides. The HSA-ICG-iRGD NPs are then applied to perform active-targeted NIR-II fluorescence imaging, resulting in a signal-to-background ratio of 6.85 in orthotopic glioma mouse models. Under the selected laser irradiation of 808 nm, the photothermal effect of HSA-ICG-iRGD extends the survival of the tumor-bearing mice to 55 days, significantly longer than that of the control group (30 days). These results highlight the potential of miniature NPs for active-targeted NIR-II fluorescence imaging and phototherapy of brain tumors.

Cell-Membrane Biomimetic Indocyanine Green Liposomes for Phototheranostics of Echinococcosis.

Echinococcosis is an important zoonotic infectious disease that seriously affects human health. Conventional diagnosis of echinococcosis relies on the application of large-scale imaging equipment, which is difficult to promote in remote areas. Meanwhile, surgery and chemotherapy for echinococcosis can cause serious trauma and side effects. Thus, the development of simple and effective treatment strategies is of great significance for the diagnosis and treatment of echinococcosis. Herein, we designed a phototheranostic system utilizing neutrophil-membrane-camouflaged indocyanine green liposomes (Lipo-ICG) for active targeting the near-infrared fluorescence diagnosis and photothermal therapy of echinococcosis. The biomimetic Lipo-ICG exhibits a remarkable photo-to-heat converting performance and desirable active-targeting features by the inflammatory chemotaxis of the neutrophil membrane. In-vitro and in-vivo studies reveal that biomimetic Lipo-ICG with high biocompatibility can achieve in-vivo near-infrared fluorescence imaging and phototherapy of echinococcosis in mouse models. Our research is the first to apply bionanomaterials to the phototherapy of echinococcosis, which provides a new standard for the convenient and noninvasive detection and treatment of zoonotic diseases.

Temperature-Feedback Nanoplatform for NIR-II Penta-Modal Imaging-Guided Synergistic Photothermal Therapy and CAR-NK Immunotherapy of Lung Cancer.

In this study, to visually acquire all-round structural and functional information of lung cancer while performing synergistic photothermal therapy (PTT) and tumor-targeting immunotherapy, a theranostic nanoplatform that introduced upconversion nanoparticles (UCNPs) and IR-1048 dye into the lipid-aptamer nanostructrure (UCILA) is constructed. Interestingly, the IR-1048 dye grafted into the lipid bilayer can serve as the theranostic agent for photoacoustic imaging, optical coherence tomography angiography, photothermal imaging, and PTT in the second near infrared (NIR-II) window. In addition, loaded in the inner part of UCILA, UCNPs possess the superior luminescence property and high X-ray attenuation coefficient, which can act as contrast agents for computed tomography (CT) and thermo-sensitive up-conversion luminescence (UCL) imaging, enabling real-time tracking of metabolic activity of tumor and temperature-feedback PTT. Furthermore, under the complementary guidance of penta-modal imaging and an accurate monitoring of in situ temperature change during PTT, UCILA exhibits its excellent capability for ablating the lung tumor with minimal side effects. Meanwhile, synergistic CAR-NK immunotherapy is carried out specifically to eradicate any possible residual tumor cells after PTT. Therefore, the UCILA nanoplatform is demonstrated as a multifunctional theranostic agent for both penta-modal imaging and temperature-feedback PTT while conducting targeting immunotherapy of lung cancer.

Active-Targeting NIR-II Phototheranostics in Multiple Tumor Models Using Platelet-Camouflaged Nanoprobes.

Cancer phototheranostics in the second near-infrared window (NIR-II, 1000-1700 nm) has recently attracted much attention owing to its high efficacy and good safety compared with that in the first near-infrared window (NIR-I, 650-950 nm). However, the lack of theranostic nanoagents with active-targeting features limits its further application in cancer precision therapies. Herein, we constructed platelet-camouflaged nanoprobes with active-targeting characteristics for NIR-II cancer phototheranostics. The as-prepared biomimetic nanoprobes can not only escape phagocytosis by macrophages but also specifically bind to CD44 on the surface of most cancer cells. We evaluated the active-targeting performance of biomimetic nanoprobes in pancreatic cancer, breast cancer, and glioma mouse models and achieved NIR-II photoacoustic imaging with a high signal-to-background ratio and photothermal treatment with excellent tumor growth inhibition. Our results show the great potential of platelet-camouflaged nanoprobes with NIR-II active-targeting features for cancer precision diagnosis and efficient therapies.

NIR II-Excited and pH-Responsive Ultrasmall Nanoplatform for Deep Optical Tissue and Drug Delivery Penetration and Effective Cancer Chemophototherapy.

The limited tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall drug delivery nanoplatform was fabricated based on BSA-stabilized CuS nanoparticles (BSA@CuS NPs). The BSA@CuS NPs effectively encapsulated doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles (BSA@CuS@DOX NPs). The BSA@CuS@DOX NPs had an ultrasmall size, which allowed them to achieve deeper tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in tumor sites, induced tumor hyperthermia, and generated remarkably high ROS levels in tumor sites upon NIR-II laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of chemotherapy and phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep tumor penetration as an effective antitumor therapy.

Molecular Engineering of Near-Infrared Light-Responsive BODIPY-Based Nanoparticles with Enhanced Photothermal and Photoacoustic Efficiencies for Cancer Theranostics.

Background: Engineering a single organic-molecule-based nanoparticle integrating precise diagnosis and effective therapy is of great significance for cancer treatment and future clinical applications but remains a great challenge. The goal of this study is to explore small organic molecule-based nanoparticles with high photothermal conversion efficiency for photoacoustic imaging-guided therapy. Methods: Heptacyclic B, O-chelated BODIPY structure (namely Boca-BODIPY) with strong near-infrared (NIR) absorption was designed as a theranostic agent through simply molecular engineering, in which heavy atoms and alkyl chains were introduced to promote its application for tumor theranostics. The Boca-BODIPY molecules are further encapsulated in reduced bovine serum albumin (BSA) through self-assembly. Results: The BSA-Boca-BODIPY exhibited excellent biocompatibility, extraordinary stability and high photothermal conversion efficiency up to 58.7%. The nanoparticles could dramatically enhance photoacoustic contrast of the tumor region, and the signal-to-noise ratio was increased about 14 times at 10 h post intravenous injection in 4T1 tumor-bearing mice. In addition, the nanoassemblies can efficiently convert laser energy (808 nm, 0.75 w cm-2, 5min) into hyperthermia for tumor ablation. Under the photoacoustic imaging-guided photothermal therapy (PTT), the 4T1 cancer cells were efficiently killed, no tumor recurrence and PTT-induced toxicity is observed. Conclusions: Molecular engineering is a promising way to design organic-molecule-based nanoparticles for cancer theranostics. Other organic-molecule-based nanoparticles which show great promise for imaging-guided cancer precision therapy can be engineered through this method.

pH-sensitive loaded retinal/indocyanine green micelles as an "all-in-one" theranostic agent for multi-modal imaging in vivo guided cellular senescence-photothermal synergistic therapy.

In this study, pH-sensitive loaded retinal/indocyanine green (ICG) micelles were developed to realize novel approaches for cellular senescence-photothermal synergistic therapy to treat cancer. The micelles could enable effective multi-modal imaging in vivo guided therapy and show anticancer activity in vitro and in vivo with satisfactory biosafety.

Engineering biocompatible benzodithiophene-based polymer dots with tunable absorptions as high-efficiency theranostic agents for multiscale photoacoustic imaging-guided photothermal therapy.

To date, photoacoustic imaging (PAI) and PAI-guided photothermal therapy (PTT) have been performed for noninvasive cancer diagnosis and precise ablation of tumors. To conduct concurrent PAI and PTT, it is essential to develop theranostic agents with strong optical absorption and high photothermal transfer efficiency. In this study, we have engineered theranostic agents with tunable absorptions based on conjugated polymer dots (Pdots) with different structures via the simple precipitation method. The as-synthesized Pdots exhibit strong absorption, high biocompatibility, and superior stability. In addition, the Pdots demonstrate that they can serve as contrast agents for multiscale PAI in vitro and in vivo. More importantly, a high photothermal conversion efficiency up to 40% is reached under irradiation with LED light, resulting in effective cancer treatment with extremely low light dose. Consequently, they show the potential as imaging-guided therapeutic agents for clinical cancer treatment and various biomedical applications.

Highly Stable Conjugated Polymer Dots as Multifunctional Agents for Photoacoustic Imaging-Guided Photothermal Therapy.

Theranostic nanomedicines involved in photothermal therapy (PTT) have received constant attention as promising alternatives to traditional therapies in clinic. However, most photothermal agents are limited by their instability and low photothermal conversion efficiency. In this study, we report new conjugated polymer dots (Pdots) as multifunctional agents for photoacoustic (PA) imaging-guided PTT. The novel 4,8-bis[5-(2-ethylhexyl)thiophen-2-yl]-2,6-bis(trimethylstannyl)benzo[1,2-b:4,5-b']dithiophene-6,6'-dibromo-N,N'-(2-ethylhexyl)isoindigo (BDT-IID) Pdots are readily fabricated though nanoreprecipitation and can absorb strongly in the 650-700 nm region. Furthermore, the BDT-IID Pdots possess a stable nanostructure and an extremely low biotoxicity. In particular, its photothermal conversion efficiency can be up to 45%. More importantly, our in vivo results exhibit that the BDT-IID Pdots are able to offer concurrently enhanced PA contrast and sufficient photothermal effect. Consequently, the BDT-IID Pdots can be exploited as a unique theranostic nanoplatform for PA imaging-guided PTT of tumors, holding great promise for their clinical translational development.

Highly absorbing multispectral near-infrared polymer nanoparticles from one conjugated backbone for photoacoustic imaging and photothermal therapy.

Semiconducting polymers with specific absorption are useful in various applications, including organic optoelectronics, optical imaging, and nanomedicine. However, the optical absorption of a semiconducting polymer with a determined structure is hardly tunable when compared with that of inorganic semiconductors. In this work, we show that the optical absorption of polymer nanoparticles from one conjugated backbone can be effectively tuned through judicious design of the particle morphology and the persistence length of polymers. Highly absorbing near-infrared (NIR) polymers based on diketopyrrolopyrrole-dithiophene (DPP-DT) are synthesized to have different molecular weights (MWs). The DPP-DT polymer with a large molecular weight and high persistence length exhibited remarkably high optical absorption with a peak mass extinction coefficient of 81.7 L g-1 cm-1, which is one of the highest value among various photothermal agents reported to date. Particularly, the polymer nanoparticles with different sizes exhibit broadly tunable NIR absorption peaks from 630 to 811 nm. The PEGylated small polymer dots (Pdots) show good NIR light-harvesting efficiency and high non-radiative decay rates, resulting in a relatively high photothermal conversion efficiency in excess of 50%. Thus, this Pdot-based platform can serve as promising photothermal agents and photoacoustic probes for cancer theranostics.

Smart human serum albumin-indocyanine green nanoparticles generated by programmed assembly for dual-modal imaging-guided cancer synergistic phototherapy.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a light-activated local treatment modality that is under intensive preclinical and clinical investigations for cancer. To enhance the treatment efficiency of phototherapy and reduce the light-associated side effects, it is highly desirable to improve drug accumulation and precision guided phototherapy for efficient conversion of the absorbed light energy to reactive oxygen species (ROS) and local hyperthermia. In the present study, a programmed assembly strategy was developed for the preparation of human serum albumin (HSA)-indocyanine green (ICG) nanoparticles (HSA-ICG NPs) by intermolecular disulfide conjugations. This study indicated that HSA-ICG NPs had a high accumulation with tumor-to-normal tissue ratio of 36.12±5.12 at 24 h and a long-term retention with more than 7 days in 4T1 tumor-bearing mice, where the tumor and its margin, normal tissue were clearly identified via ICG-based in vivo near-infrared (NIR) fluorescence and photoacoustic dual-modal imaging and spectrum-resolved technology. Meanwhile, HSA-ICG NPs efficiently induced ROS and local hyperthermia simultaneously for synergetic PDT/PTT treatments under a single NIR laser irradiation. After an intravenous injection of HSA-ICG NPs followed by imaging-guided precision phototherapy (808 nm, 0.8 W/cm2 for 5 min), the tumor was completely suppressed, no tumor recurrence and treatments-induced toxicity were observed. The results suggest that HSA-ICG NPs generated by programmed assembly as smart theranostic nanoplatforms are highly potential for imaging-guided cancer phototherapy with PDT/PTT synergistic effects.

Robust ICG theranostic nanoparticles for folate targeted cancer imaging and highly effective photothermal therapy.

Folic acid (FA)-targeted indocyanine green (ICG)-loaded nanoparticles (NPs) (FA-INPs) were developed to a near-infrared (NIR) fluorescence theranostic nanoprobe for targeted imaging and photothermal therapy of cancer. The FA-INPs with good monodispersity exhibited excellent size and fluorescence stability, preferable temperature response under laser irradiation, and specific molecular targeting to MCF-7 cells with FA receptor overexpression, compared to free ICG. The FA-INPs enabled NIR fluorescence imaging to in situ monitor the tumor accumulation of the ICG. The cell survival rate assays in vitro and photothermal therapy treatments in vivo indicated that FA-INPs could efficiently targeted and suppressed MCF-7 cells and xenograft tumors. Hence, the FA-INPs are notable theranostic NPs for imaging-guided cancer therapy in clinical application.