A Multispectral Photoacoustic Tracking Strategy for Wide-Field and Real-Time Monitoring of Macrophages in Inflammation.

Inflammation is a common defensive response of the vascular system that involves the activation and mediation of immune cell and stem cell homing. However, it is usually hard to track and analyze the real-time status of these cell types toward the inflammation microenvironment in a large field of view with desired resolution. Here, we designed and synthesized near-infrared absorbing semiconducting polymer nanoparticles, BBT-TQP-NP (BTNPs), as the cell tracker and utilized their photoacoustic activity to unveil the targeting behaviors of macrophages, neutrophils, and mesenchymal stem cells to the inflamed sites in mice. Facilitated by multispectral optical-resolution photoacoustic microscopy (ORPAM), we can continuously monitor the in vivo photoacoustic signals of the labeled cells with cellular resolution in a wide-field (a circle field-of-view with a diameter of 9 mm). In addition, the highly sensitive observation of vascular microstructures and labeled cells can reveal the time-dependent accumulating behaviors of various cell types toward inflammation sites. As a result, our study offers an effective and promising tracking strategy to analyze the in vivo status and fate of functional cells in targeting the diseased/damaged regions.

Design of One-for-All Near-Infrared Aggregation-Induced Emission Nanoaggregates for Boosting Theranostic Efficacy.

Fluorescence-guided phototherapy, including photodynamic and photothermal therapy, is considered an emerging noninvasive strategy for cancer treatments. Organic molecules are promising theranostic agents because of their facile construction, simple modification, and good biocompatibility. Organic systems that integrated multifunctionalities in a single component and achieved high efficiency in both imaging and therapies are rarely reported as the inherently competitive energy relaxation pathways are hard to modulate, and fluorescence quenching occurs upon molecular aggregation. Herein, a versatile theranostic platform with near-infrared emission, high fluorescence quantum yield, robust reactive oxygen species production, and excellent photothermal conversion efficiency was developed based on an aggregation-induced emission luminogen, namely, TPA-TBT. In vivo studies revealed that the TPA-TBT nanoaggregates exhibit outstanding photodynamic and photothermal therapy efficacy to ablate tumors inoculated in a mouse model. This work offers a design strategy to develop one-for-all cancer theranostic agents by modulating and utilizing the relaxation energy of excitons in full.

Fast Delivery of Multifunctional NIR-II Theranostic Nanoaggregates Enabled by the Photoinduced Thermoacoustic Process.

Multifunctional nanoaggregates are widely used in cancer phototheranostics. However, it is challenging to construct their multifunctionality with a single component, and deliver them rapidly and efficiently without complex modifications. Herein, a NIR-absorbing small molecule named TBT-2(TP-DPA) is designed and certify its theranostic potentials. Then, their nanoaggregates, which are simply encapsulated by DSPE-PEG, demonstrate a photothermal efficiency of 51% while keeping a high photoluminescence quantum yield in the NIR region. Moreover, the nanoaggregates can be excited and delivered by an 808 nm pulse laser to solid tumors within only 40 min. The delivery efficiency and theranostic efficacy are better than that of the traditional enhanced permeability and retention (EPR) effect (generally longer than 24 hours). This platform is first termed as the photoinduced thermoacoustic (PTA) process, and confirm its application requires both NIR-responsive materials and pulse laser irradiation. This study not only inspires the design of multifunctional nanoaggregates, but also offers a feasible approach to their fast delivery. The platform reported here provides a promising prospect to boost the development of multifunctional theranostic drugs and maximize the efficacy of used medicines for their clinical applications.

Single-cell spatiotemporal analysis reveals cell fates and functions of transplanted mesenchymal stromal cells during bone repair.

Mesenchymal stromal cells (MSCs) transplantation could enhance bone repair. However, the cell fate of transplanted MSCs, in terms of their local distribution and spatial associations with other types of cells were poorly understood. Here, we developed a single-cell 3D spatial correlation (sc3DSC) method to track transplanted MSCs based on deep tissue microscopy of fluorescent nanoparticles (fNPs) and immunofluorescence of key proteins. Locally delivered fNP-labeled MSCs enhanced tibial defect repair, increased the number of stem cells and vascular maturity in mice. fNP-MSCs persisted in the defect throughout repair. But only a small portion of transplanted cells underwent osteogenic differentiation (OSX+); a significant portion has maintained their expression of mesenchymal stem cell and skeletal stem cell markers (SCA-1 and PRRX1). Our results contribute to the optimization of MSC-based therapies. The sc3DSC method may be useful in studying cell-based therapies for the regeneration of other tissue types or disease models.

Conjugated Oligoelectrolytes for Long-Term Tumor Tracking with Incremental NIR-II Emission.

The design and synthesis of the near-infrared (NIR)-II emissive conjugated oligoelectrolyte COE-BBT are reported. COE-BBT has a solubility in aqueous media greater than 50 mg mL-1 , low toxicity, and a propensity to intercalate lipid bilayers, wherein it exhibits a higher emission quantum yield relative to aqueous media. Addition of COE-BBT to cells provides two emission channels, at ≈500 and ≈1020 nm, depending on the excitation wavelength, which facilitates in vitro confocal microscopy and in vivo animal imaging. The NIR-II emission of COE-BBT is used to track intracranial and subcutaneous tumor progression in mice. Of relevance is that the total NIR-II intensity increases over time. This phenomenon is attributed to a progressive attenuation of a COE-BBT self-quenching effect within the cells due to the expected dye dilution per cell as the tumor proliferates.

Targeted NIR-II emissive nanoprobes for tumor detection in mice and rabbits.

The functional NIR-II emissive nanoprobe loaded with AIEgen (cRGD-TTB NPs) achieved a high quantum yield (10.32%) and a high signal-to-background (S/B) ratio of 7.7 when employed for the visualization of large tumors (∼600 mm3) in rabbit models for the first time. This work will aid in the investigation of tumor targeting effect of therapeutic agents in large animal models.

Efficient and precise delivery of microRNA by photoacoustic force generated from semiconducting polymer-based nanocarriers.

One major challenge in miRNA-based therapy is to explore facile delivery strategies, which can facilitate the efficient and precise accumulation of intrinsically instable microRNAs (miRNAs) at targeted tumor sites. To address this critical issue, for the first time we demonstrate that a near-infrared (NIR) pulse laser can guide efficient delivery of miRNAs mediated by a NIR-absorbing and photoacoustic active semiconducting polymer (SP) nanocarrier, which can generate photoacoustic radiation force to intravascularly overcome the endothelial barriers. Importantly, we demonstrate an ultrafast delivery of miRNA (miR-7) to tumor tissues under the irradiation of pulse laser in 20 min, showing a 5-fold boosted efficiency in comparison to the traditional passive targeting strategy. The delivered miR-7 acts as a sensitizer of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and synergizes with TRAIL-inducing compound (TIC), leading to sustained TRAIL upregulation for effective tumor suppression in mice. As such, our results indicate that the NIR-absorbing semiconducting polymer-mediated nanocarrier platform can significantly enhance the targeted delivery efficiency of therapeutic miRNAs to tumors, resulting in potent tumor growth inhibition.

Photoacoustic Force-Guided Precise and Fast Delivery of Nanomedicine with Boosted Therapeutic Efficacy.

Precise and efficient delivery of nanomedicine to the target site has remained as a major roadblock in advanced cancer treatment. Here, a novel photoacoustic force (PAF)-guided nanotherapeutic system is reported based on a near-infrared (NIR)-absorbing semiconducting polymer (SP), showing significantly improved tumor accumulation and deep tissue penetration for enhanced phototherapeutic efficacy. The accumulation of nanoparticles in 4T1 tumor-bearing mice induced by the PAF strategy displays a fivefold enhancement in comparison with that of the traditional passive targeting pathway, in a significantly shortened time (45 min vs 24 h) with an enhanced penetration depth in tumors. Additionally, a tumor-bearing mouse model is rationally designed to unveil the mechanism, indicating that the nanoparticles enter solid tumors through enhanced transportation across blood vessel barriers via both inter-endothelial gaps and active trans-endothelial pathways. This process is specifically driven by PAF generated from the nanoparticles under NIR laser irradiation. The study thus demonstrates a new nanotherapeutic strategy with low dose, enhanced delivery efficiency in tumor, and boosted therapeutic efficacy, opening new doors for designing novel nanocarriers.