simultaneously achieve high contrast, good spatiotemporal resolution, deep penetration, and good sensitivity. [7][8][9][10] Although conventional in vivo NIR-I brain fluorescence imaging has advantages in high sensitivity, good temporal resolution, and real-time wide-field image, it suffers from low penetration, non-negligible autofluorescence, and scattering-limited spatial resolution. [7,11] On the other hand, brain photoacoustic (PA) imaging (PAI) with reconstruction of acoustic waves generated by light absorbers after pulsed NIR laser illumination has demonstrated good ultrasonic spatial resolution, and much deeper penetration than fluorescence imaging, because ultrasound attenuates far less than light in vivo. [12] However, conventional PAI often shows severe background interference owing to the negligible tissue absorbance within NIR-I region. [9,12] In addition, multimodal brain imaging with combined desirable features of different imaging modalities could overcome shortcomings of single modality and improve diagnostic accuracy. [2,8,9,13] So far, multimodal imaging generally requires administration of different contrast agents or nanoparticles (NPs) containing multiple components, [2,8,13] which faces the challenges of different location for the former and low NP reproducibility for the latter. It is Diagnostics of cerebrovascular structures and microscopic tumors with intact blood-brain barrier (BBB) significantly contributes to timely treatment of patients bearing neurological diseases. Dual NIR-II fluorescence and photoacoustic imaging (PAI) is expected to offer powerful strength, including good spatiotemporal resolution, deep penetration, and large signal-to-background ratio (SBR) for precise brain diagnostics. Herein, biocompatible and photostable conjugated polymer nanoparticles (CP NPs) are reported for dualmodality brain imaging in the NIR-II window. Uniform CP NPs with a size of 50 nm are fabricated from microfluidics devices, which show an emission peak at 1156 nm with a large absorptivity of 35.2 L g −1 cm −1 at 1000 nm. The NIR-II fluorescence imaging resolves hemodynamics and cerebral vasculatures with a spatial resolution of 23 µm at a depth of 600 µm. The NIR-II PAI enables successful noninvasive mapping of deep microscopic brain tumors (<2 mm at a depth of 2.4 mm beneath dense skull and scalp) with an SBR of 7.2 after focused ultrasound-induced BBB opening. This study demonstrates that CP NPs are promising contrast agents for brain diagnostics. Brain ImagingClear pinpointing of cerebral vasculature and tumor structures with different morphologies and biology characteristics in complex central neural system significantly benefits patients bearing brain pathologies like neurological disorder, traumatic injury, stroke, Alzheimer's disease, and even early-and late-stage tumors. [1][2][3][4][5][6][7][8][9] Conventional neuroimaging modalities exhibit certain intrinsic limitations in each modality, which could not

Exogenous contrast‐agent‐assisted NIR‐II optical‐resolution photoacoustic microscopy imaging (ORPAMI) holds promise to decipher wide‐field 3D biological structures with deep penetration, large signal‐to‐background ratio (SBR), and high maximum imaging depth to depth resolution ratio. Herein, NIR‐II conjugated polymer nanoparticle (CP NP) assisted ORPAMI is reported for pinpointing cerebral and tumor vasculatures. The CP NPs exhibit a large extinction coefficient of 48.1 L g−1 at the absorption maximum of 1161 nm, with an ultrahigh PA sensitivity up to 2 µg mL−1. 3D ORPAMI of wide‐field mice ear allows clear visualization of regular vasculatures with a resolution of 19.2 µm and an SBR of 29.3 dB at the maximal imaging depth of 539 µm. The margin of ear tumor composed of torsional dense vessels among surrounding normal regular vessels can be clearly delineated via 3D angiography. In addition, 3D whole‐cortex cerebral vasculatures with large imaging area (48 mm2), good resolution (25.4 µm), and high SBR (22.3 dB) at a depth up to 1001 µm are clearly resolved through the intact skull. These results are superior to the recently reported 3D NIR‐II fluorescence confocal vascular imaging, which opens up new opportunities for NIR‐II CP‐NP‐assisted ORPAMI in various biomedical applications.

Organic photothermal nanoagents are promising candidates for treating primary tumors and inhibiting metastasis. However, they often exhibit poor photostability, low absorptivity, or limited photothermal conversion efficiency (PCE). Herein, a facile molecular engineering approach to produce efficient organic photothermal molecules is demonstrated. By integrating donoracceptor structure and molecular motors, a small molecule (TA1) is synthesized with large absorptivity (22.4 L g −1 cm −1 ), negligible reactive oxygen species generation, high PCE (84.8%), excellent photothermal stability, and good biocompatibility. Furthermore, microfluidics is used to thoroughly study the relationship between the size and process conditions, yielding small uniform nanoparticles (NPs) with a diameter of 44 nm. Importantly, TA1 NPs under near-infrared laser irradiation significantly suppressed primary breast tumor growth and metastasis, both in vitro and in vivo. This study shows that small organic molecule nanoparticles are promising candidates for future cancer nanomedicine.

Photothermal therapy (PTT) has shown great promise to spatiotemporally ablate cancer cells, and further understanding of the immune system response to PTT treatment would contribute to improvement in therapeutic outcomes. Herein, we utilize microfluidic technology to prepare biocompatible conjugated polymer nanoparticles (CP NPs) as PTT agents and assess the immune response triggered by CP-based PTT treatment in vitro and in vivo. Through careful control of the antisolvent, CP NPs with a uniform diameter of 52 nm were obtained. The c-RGD-functionalized CP NPs exhibit high photothermal conversion efficiency, inducing effective cancer cell death under an 808 nm laser illumination. Using macrophage cells as the model, CP NPs demonstrate effective activation of proinflammatory immune response. Furthermore, in tumor-bearing mice model, a single round of CP NP-assisted PTT could efficiently induce antitumor immunity activation and ultimately inhibit tumor growth. The study provides detailed understanding of both microfluidic technology for CP NP fabrication and photothermal-triggered antitumor immune responses.

Organic particles have attracted extensive attention due to their broad scientific and industrial applications. Solvents play important roles in producing organic particles with fine-tuned sizes, shapes, and surface morphologies, thus the advancement of microfluidic devices with a thorough understanding of solvent miscibility offers additional opportunities to fabricate organic particles in large quantities. In this issue of ACS Nano, Chen et al. report that solvents could play a seemingly magical role in switching both reaction directions and particle morphologies from the same starting materials. Through monitoring the particle formulation kinetics, both social self-sorting and narcissistic self-sorting mechanisms have been proposed, which offer powerful methods to yield organic particles with desirable shapes and compositions.

Dual-functional aggregation-induced photosensitizers (AIE-PSs) with singlet oxygen generation (SOG) ability and bright fluorescence in aggregated state have received much attention in image-guided photodynamic therapy (PDT). However, designing an AIE-PS with both high SOG and intense fluorescence via molecular design is still challenging. In this work, we report a new nanohybrid consisting of gold nanostar (AuNS) and AIE-PS dots with enhanced fluorescence and photosensitization for theranostic applications. The spectral overlap between the extinction of AuNS and fluorescence emission of AIE-PS dots (665 nm) is carefully selected using five different AuNSs with distinct localized surface plasmon (LSPR) peaks. Results show that all the AuNSs can enhance the 1O2 production of AIE-PS dots, among which the AuNS with LSPR peak at 585 nm exhibited the highest 1O2 enhancement factor of 15-fold with increased fluorescence brightness. To the best of our knowledge, this is the highest enhancement factor reported for the metal-enhanced singlet oxygen generation systems. The Au585@AIE-PS nanodots were applied for simultaneous fluorescence imaging and photodynamic ablation of HeLa cancer cells with strongly enhanced PDT efficiency in vitro. This study provides a better understanding of the metal-enhanced AIE-PS nanohybrid systems, opening up new avenue towards advanced image-guided PDT with greatly improved efficacy.

Polymeric nanoparticles play important roles in the delivery of a multitude of therapeutic and imaging contrast agents. Although these nanomaterials have shown tremendous potential in disease diagnosis and therapy, there have been many reports on the failure of these nanoparticles in realizing their intended objectives due to an individual or a combination of factors, which have collectively challenged the merit of nanomedicine for disease theranostics. Herein, we investigate the interactions of polymeric nanoparticles with biological entities from molecular to organism levels. Specifically, the protein corona formation, in vitro endothelial uptake, and in vivo circulation time of these nanoparticles are systematically probed. We identify the crucial role of nanocarrier lipophilicity, zeta-potential, and size in controlling the interactions between nanoparticles and biological systems and propose a two-step framework in formulating a single nanoparticle system to regulate multiple biological effects. This study provides insight into the rational design and optimization of the performance of polymeric nanoparticles to advance their theranostic and nanomedicine applications.

We report a new enhanced solvent displacement method for the synthesis of highly monodisperse nanoparticles with direct visualization of the ouzo zone.