Afterglow optical agents, which emit light long after cessation of excitation, hold promise for ultrasensitive in vivo imaging because they eliminate tissue autofluorescence. However, afterglow imaging has been limited by its reliance on inorganic nanoparticles with relatively low brightness and short-near-infrared (NIR) emission. Here we present semiconducting polymer nanoparticles (SPNs) <40 nm in diameter that store photon energy via chemical defects and emit long-NIR afterglow luminescence at 780 nm with a half-life of ∼6 min. In vivo, the afterglow intensity of SPNs is more than 100-fold brighter than that of inorganic afterglow agents, and the signal is detectable through the body of a live mouse. High-contrast lymph node and tumor imaging in living mice is demonstrated with a signal-to-background ratio up to 127-times higher than that obtained by NIR fluorescence imaging. Moreover, we developed an afterglow probe, activated only in the presence of biothiols, for early detection of drug-induced hepatotoxicity in living mice.

Drug-induced acute kidney injury (AKI) with a high morbidity and mortality is poorly diagnosed in hospitals and deficiently evaluated in drug discovery. Here, we report the development of molecular renal probes (MRPs) with a record high renal clearance efficiency for in vivo optical imaging of drug-induced AKI. MRPs specifically activates their near-infrared fluorescence or chemiluminescence signals towards the prodromal biomarkers of AKI including superoxide anion, N-acetyl-β-D-glucosaminidase and caspase-3, enabling the first example of longitudinal imaging of multiple molecular events in the kidneys of living mice. Importantly, they in situ report the sequential occurrence of oxidative stress, lysosomal damage and cellular apoptosis, which precedes clinical manifestation of AKI (decreased glomerular filtration). Such an active imaging mechanism allows MRPs to noninvasively detect the onset of cisplatin-induced AKI at least 36 h earlier than the existing imaging methods. MRPs can also act as exogenous tracers for optical urinalysis that outperforms typical clinical/preclinical assays, demonstrating their clinical promise for early diagnosis of AKI.

Optogenetics provides powerful means for precise control of neuronal activity; however, the requirement of transgenesis and the incapability to extend the neuron excitation window into the deep-tissue-penetrating near-infrared (NIR) region partially limit its application. We herein report a potential alternative approach to optogenetics using semiconducting polymer nanobioconjugates (SPNsbc) as the photothermal nanomodulator to control the thermosensitive ion channels in neurons. SPNsbc are designed to efficiently absorb the NIR light at 808 nm and have a photothermal conversion efficiency higher than that of gold nanorods. By virtue of the fast heating capability in conjunction with the precise targeting to the thermosensitive ion channel, SPNsbc can specifically and rapidly activate the intracellular Ca(2+) influx of neuronal cells in a reversible and safe manner. Our study provides an organic nanoparticle based strategy that eliminates the need for genetic transfection to remotely regulate cellular machinery.

Optical theranostic nanoagents that seamlessly and synergistically integrate light-generated signals with photothermal or photodynamic therapy can provide opportunities for cost-effective precision medicine, while the potential for clinical translation requires them to have good biocompatibility and high imaging/therapy performance. We herein report an intraparticle molecular orbital engineering approach to simultaneously enhance photoacoustic brightness and photothermal therapy efficacy of semiconducting polymer nanoparticles (SPNs) for in vivo imaging and treatment of cancer. The theranostic SPNs have a binary optical component nanostructure, wherein a near-infrared absorbing semiconducting polymer and an ultrasmall carbon dot (fullerene) interact with each other to induce photoinduced electron transfer upon light irradiation. Such an intraparticle optoelectronic interaction augments heat generation and consequently enhances the photoacoustic signal and maximum photothermal temperature of SPNs by 2.6- and 1.3-fold, respectively. With the use of the amplified SPN as the theranostic nanoagent, it permits enhanced photoacoustic imaging and photothermal ablation of tumor in living mice. Our study thus not only introduces a category of purely organic optical theranostics but also highlights a molecular guideline to amplify the effectiveness of light-intensive imaging and therapeutic nanosystems.

Photoacoustic (PA) imaging holds great promise for preclinical research and clinical practice. However, most studies rely on the laser wavelength in the first near-infrared (NIR) window (NIR-I, 650-950 nm), while few studies have been exploited in the second NIR window (NIR-II, 1000-1700 nm), mainly due to the lack of NIR-II absorbing contrast agents. We herein report the synthesis of a broadband absorbing PA contrast agent based on semiconducting polymer nanoparticles (SPN-II) and apply it for PA imaging in NIR-II window. SPN-II can absorb in both NIR-I and NIR-II regions, providing the feasibility to directly compare PA imaging at 750 nm with that at 1064 nm. Because of the weaker background PA signals from biological tissues in NIR-II window, the signal-to-noise ratio (SNR) of SPN-II resulted PA images at 1064 nm can be 1.4-times higher than that at 750 nm when comparing at the imaging depth of 3 cm. The proof-of-concept application of NIR-II PA imaging is demonstrated in in vivo imaging of brain vasculature in living rats, which showed 1.5-times higher SNR as compared with NIR-I PA imaging. Our study not only introduces the first broadband absorbing organic contrast agent that is applicable for PA imaging in both NIR-I and NIR-II windows but also reveals the advantages of NIR-II over NIR-I in PA imaging.

Phototheranostic nanoagents are promising for early diagnosis and precision therapy of cancer. However, their imaging ability and therapeutic efficacy are often limited due to the presence of delivery barriers in the tumor microenvironment. Herein, we report the development of organic multimodal phototheranostic nanoagents that can biomimetically target cancer-associated fibroblasts in the tumor microenvironment for enhanced multimodal imaging-guided cancer therapy. Such biomimetic nanocamouflages comprise a near-infrared (NIR) absorbing semiconducting polymer nanoparticle (SPN) coated with the cell membranes of activated fibroblasts. The homologous targeting mechanism allows the activated fibroblast cell membrane coated SPN (AF-SPN) to specifically target cancer-associated fibroblasts, leading to enhanced tumor accumulation relative to the uncoated and cancer cell membrane coated counterparts after systemic administration in living mice. As such, AF-SPN not only provides stronger NIR fluorescence and photoacoustic signals to detect tumors but also generates enhanced cytotoxic heat and singlet oxygen to exert combinational photothermal and photodynamic therapy, ultimately leading to an antitumor efficacy higher than that of the counterparts. This study introduces an organic phototheranostic system that biomimetically targets the component in the tumor microenvironment for enhanced multimodal cancer theranostics.

Theranostic nanoagents are promising for precision medicine. However, biodegradable nanoagents with the ability for photoacoustic (PA) imaging guided photothermal therapy (PTT) are rare. We herein report the development of biodegradable semiconducting polymer nanoparticles (SPNs) with enhanced PA and PTT efficacy for cancer therapy. The design capitalizes on the enzymatically oxidizable nature of vinylene bonds in conjunction with polymer chemistry to synthesize a biodegradable semiconducting polymer (DPPV) and transform it into water-soluble nanoparticles (SPNV). As compared with its counterpart SPN (SPNT), the presence of vinylene bonds within the polymer backbone also endows SPNV with a significantly enhanced mass absorption coefficient (1.3-fold) and photothermal conversion efficacy (2.4-fold). As such, SPNV provides the PA signals and the photothermal maximum temperature higher than SPNT, allowing detection and photothermal ablation of tumors in living mice in a more sensitive and effective way. Our study thus reveals a general molecular design to enhance the biodegradability of optically active polymer nanoparticles while dramatically elevating their imaging and therapeutic capabilities.

An activatable photoacoustic nanoprobe based on a semiconducting oligomer with amplified brightness and pH-sensing capability is developed by taking advantage of nanodoping to simultaneously create both intraparticle photoinduced electron transfer and intramolecular protonation within a single particle. This organic nanoprobe permits noninvasive real-time ratiometric photoacoustic imaging of pH in tumors in living mice through systemic administration at a relatively low dosage.