In situ pain relief during photodynamic therapy by ROS-responsive nanomicelle through blocking VGSC.

Pain in photodynamic therapy (PDT), resulting from the stimulation of reactive oxygen species (ROS) and local acute inflammation, is a primary side effect of PDT that often leads to treatment interruption or termination, significantly compromising the efficacy of PDT and posing an enduring challenge for clinical practice. Herein, a ROS-responsive nanomicelle, poly(ethylene glycol)-b-poly(propylene sulphide) (PEG-PPS) encapsulated Ce6 and Lidocaine (LC), (ESCL) was used to address these problems. The tumor preferentially accumulated micelles could realize enhanced PDT effect, as well as in situ quickly release LC due to its ROS generation ability after light irradiation, which owes to the ROS-responsive property of PSS. In addition, PSS can suppress inflammatory pain which is one of the mechanisms of PDT induced pain. High LC-loaded efficiency (94.56 %) owing to the presence of the thioether bond of the PPS made an additional pain relief by inhibiting excessive inflammation besides blocking voltage-gated sodium channels (VGSC). Moreover, the anti-angiogenic effect of LC offers further therapeutic effects of PDT. The in vitro and in vivo anti-tumor results revealed significant PDT efficacy. The signals of the sciatic nerve in mice were measured by electrophysiological study to evaluate the pain relief, results showed that the relative integral area of neural signals in ESCL-treated mice decreased by 49.90 % compared to the micelles without loaded LC. Therefore, our study not only develops a very simple but effective tumor treatment PDT and in situ pain relief strategy during PDT, but also provides a quantitative pain evaluation method.

In situ sustained release hydrogel system delivering GLUT1 inhibitor and chemo-drug for cancer post-surgical treatment.

Systematic administration of small molecular drugs often suffered from the low efficacy and systemic toxicity in cancer therapy. In addition, application of single mode drug usually leads to unsatisfactory therapeutic outcomes. Currently, developing multimodal-drug combination strategy that acts on different pathways without increasing side effects remains great challenge. Here, we developed a hydrogel system that co-delivered glycolysis inhibitor apigenin and chemo-drug gemcitabine to realize combination strategy for combating cancer with minimal systemic toxicity. We demonstrated that this system can not only eliminate tumor cells in situ, but also induce abscopal effect on various tumor models. These results showed that our study provided a safe and effective strategy for clinical cancer treatment.

A Multiscale Connected UNet for the Segmentation of Lung Cancer Cells in Pathology Sections Stained Using Rapid On-Site Cytopathological Evaluation.

Lung cancer is an increasingly serious health problem worldwide, and early detection and diagnosis are crucial for successful treatment. With the development of artificial intelligence and the growth of data volume, machine learning techniques can play a significant role in improving the accuracy of early detection in lung cancer. This study proposes a deep learning-based segmentation algorithm for rapid on-site cytopathological evaluation (ROSE) to enhance the diagnostic efficiency of endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA) during surgery. By utilizing the CUNet3+ network model, cell clusters, including cancer cell clusters, can be accurately segmented in ROSE-stained pathological sections. The model demonstrated high accuracy, with an F1-score of 0.9604, recall of 0.9609, precision of 0.9654, and accuracy of 0.9834 on the internal testing data set. It also achieved an area under the receiver-operating characteristic curve of 0.9972 for cancer identification. The proposed algorithm saved time for on-site diagnosis, improved EBUS-TBNA efficiency, and outperformed classical segmentation algorithms in accurately identifying lung cancer cell clusters in ROSE-stained images. It effectively reduced over-segmentation, decreased network parameters, and enhanced computational efficiency, making it suitable for real-time patient evaluation during surgical procedures.

Secondary cavitation bubble dynamics during laser-induced bubble formation in a small container.

We investigated secondary cavitation bubble dynamics during laser-induced bubble formation in a small container with a partially confined free surface and elastic thin walls. We employed high-speed photography to record the dynamics of sub-mm-sized laser-induced bubbles and small secondary bubble clouds. Simultaneous light scattering and acoustic measurements were used to detect the oscillation times of laser-induced bubbles. We observed that the appearance of secondary bubbles coincides with a prolonged collapse phase and with re-oscillations of the laser-induced bubble. We observed an asymmetric distribution of secondary bubbles with a preference for the upstream side of the focus, an absence of secondary bubbles in the immediate vicinity of the laser focus, and a migration of laser-induced bubble toward secondary bubbles at large pulse energies. We found that secondary bubbles are created through heating of impurities to form initial nanobubble nuclei, which are further expanded by rarefaction waves. The rarefaction waves originate from the vibration of the elastic thin walls, which are excited either directly by laser-induced bubble or by bubble-excited liquid-mass oscillations. The oscillation period of thin walls and liquid-mass were Twall = 116 µs and Tlm ≈ 160 µs, respectively. While the amplitude of the wall vibrations increases monotonically with the size of laser-induced bubbles, the amplitude of liquid-mass oscillation undulates with increasing bubble size. This can be attributed to a phase shift between the laser-induced bubble oscillation and the liquid-mass oscillator. Mutual interactions between the laser-induced bubble and secondary bubbles reveal a fast-changing pressure gradient in the liquid. Our study provides a better understanding of laser-induced bubble dynamics in a partially confined environment, which is of practical importance for microfluidics and intraluminal laser surgery.

Laser induced spherical bubble dynamics in partially confined geometry with acoustic feedback from container walls.

We investigated laser-induced cavitation dynamics in a small container with elastic thin walls and free or partially confined surface both experimentally and by numerical investigations. The cuvette was only 8-25 times larger than the bubble in its center. The liquid surface was either free, or two thirds were confined by a piston-shaped pressure transducer. Different degrees of confinement were realized by filling the liquid up to the transducer surface or to the top of the cuvette. For reference, some experiments were performed in free liquid. We recorded the bubble dynamics simultaneously by high-speed photography, acoustic measurements, and detection of probe beam scattering. Simultaneous single-shot recording of radius-time curves and oscillation times enabled to perform detailed investigations of the bubble dynamics as a function of bubble size, acoustic feedback from the elastic walls, and degree of surface confinement. The bubble dynamics was numerically simulated using a Rayleigh-Plesset model extended by terms describing the acoustically mediated feedback from the bubble's environment. Bubble oscillations were approximately spherical as long as no secondary cavitation by tensile stress occurred. Bubble expansion was always similar to the dynamics in free liquid, and the environment influenced mainly the collapse phase and subsequent oscillations. For large bubbles, strong confinement led to a slight reduction of maximum bubble size and to a pronounced reduction of the oscillation time, and both effects increased with bubble size. The joint action of breakdown-induced shock wave and bubble expansion excites cuvette wall vibrations, which produce alternating pressure waves that are focused onto the bubble. This results in a prolongation of the collapse phase and an enlargement of the second oscillation, or in time-delayed re-oscillations. The details of the bubble dynamics depend in a complex manner on the degree of surface confinement and on bubble size. Numerical simulations of the first bubble oscillation agreed well with experimental data. They suggest that the alternating rarefaction/compression waves from breakdown-induced wall vibrations cause a prolongation of the first oscillation. By contrast, liquid mass movement in the cuvette corners result in wall vibrations causing late re-oscillations. The strong and rich interaction between the bubble and its surroundings may be relevant for a variety of applications such as intraluminal laser surgery and laser-induced cavitation in microfluidics.

Janus Silica Nanoparticle-Based Tumor Microenvironment Modulator for Restoring Tumor Sensitivity to Programmed Cell Death Ligand 1 Immune Checkpoint Blockade Therapy.

An immunosuppressive tumor microenvironment (TME) with inadequate and exhausted tumor-infiltrating cytotoxic lymphocytes and abundant cellular immunosuppressors is the major obstacle responsible for the poor efficacy of PD-1/PD-L1 (programmed cell death 1 and its ligand 1) immune checkpoint blockade (ICB) therapy. Herein, a Janus silica nanoparticle (JSNP)-based immunomodulator is explored to reshape the TME for boosting the therapeutic outcomes of αPD-L1 therapy. The designed JSNP has two distinct domains, namely, an ultra pH-responsive side (UPS), which could encapsulate PI3Kγ inhibitor IPI549 in the pore structure, and a polycation-grafted intra-glutathione (GSH)-sensitive side (IGS), which could absorb CXCL9 cDNA on the surface. The final IPI549@UPS-IGS-PDMAEMA@CXCL9 cDNA (IUIPC) could release IPI549 in weak acid TME to target myeloid-derived suppressor cells (MDSCs) to reverse negative immunoregulation and then release CXCL9 cDNA in tumor cells with abundant GSH for sustained CXCL9 chemokine expression and secretion to improve cytotoxic lymphocyte recruitment signals, thereby jointly restoring tumor sensitivity to PD-1/PD-L1 ICB therapy. As expected, the IUIPC-mediated TME remodeling during αPD-L1 therapy significantly ameliorated TME immunosuppression, as well as induced potent systemic antitumor immune responses, which ultimately achieved a robustly boosted antitumor efficacy proven by remarkable suppression of primary tumor growth, obvious prevention of tumor recurrence, and significant regression of abscopal tumors. Hence, the IUIPC-mediated TME-regulating strategy provides an enormous perspective for the improvement of PD-1/PD-L1 ICB therapy.

Improved Simulated-Daylight Photodynamic Therapy and Possible Mechanism of Ag-Modified TiO2 on Melanoma.

Simulated-daylight photodynamic therapy (SD-PDT) may be an efficacious strategy for treating melanoma because it can overcome the severe stinging pain, erythema, and edema experienced during conventional PDT. However, the poor daylight response of existing common photosensitizers leads to unsatisfactory anti-tumor therapeutic effects and limits the development of daylight PDT. Hence, in this study, we utilized Ag nanoparticles to adjust the daylight response of TiO2, acquire efficient photochemical activity, and then enhance the anti-tumor therapeutic effect of SD-PDT on melanoma. The synthesized Ag-doped TiO2 showed an optimal enhanced effect compared to Ag-core TiO2. Doping Ag into TiO2 produced a new shallow acceptor impurity level in the energy band structure, which expanded optical absorption in the range of 400-800 nm, and finally improved the photodamage effect of TiO2 under SD irradiation. Plasmonic near-field distributions were enhanced due to the high refractive index of TiO2 at the Ag-TiO2 interface, and then the amount of light captured by TiO2 was increased to induce the enhanced SD-PDT effect of Ag-core TiO2. Hence, Ag could effectively improve the photochemical activity and SD-PDT effect of TiO2 through the change in the energy band structure. Generally, Ag-doped TiO2 is a promising photosensitizer agent for treating melanoma via SD-PDT.

MMP-2 Inhibitor-Mediated Tumor Microenvironment Regulation Using a Sequentially Released Bio-Nanosystem for Enhanced Cancer Photo-Immunotherapy.

Combining photodynamic therapy (PDT) with natural killer (NK) cell-based immunotherapy has shown great potential against cancers, but the shedding of NK group 2, member D ligands (NKG2DLs) on tumor cells inhibited NK cell activation in the tumor microenvironment. Herein, we assembled microenvironment-/light-responsive bio-nanosystems (MLRNs) consisting of SB-3CT-containing ß-cyclodextrins (ß-CDs) and photosensitizer-loaded liposomes, in which SB-3CT was considered to remodel the tumor microenvironment. ß-CDs and liposomes were linked by metalloproteinase 2 (MMP-2) responsive peptides, enabling sequential release of SB-3CT and chlorin e6 triggered by the MMP-2-abundant tumor microenvironment and 660 nm laser irradiation, respectively. Released SB-3CT blocked tumor immune escape by antagonizing MMP-2 and promoting the NKG2D/NKG2DL pathway, while liposomes were taken up by tumor cells for PDT. MLRN-mediated photo-immunotherapy significantly induced melanoma cell cytotoxicity (83.31%), inhibited tumor growth (relative tumor proliferation rate: 1.13% of that of normal saline) in the xenografted tumor model, and enhanced tumor-infiltrating NK cell (148 times) and NKG2DL expression (9.55 and 16.52 times for MICA and ULBP-1, respectively), achieving a synergistic effect. This study not only provided a simple insight into the development of new nanomedicine for programed release of antitumor drugs and better integration of PDT and immunotherapy but also a novel modality for clinical NK cell-mediated immunotherapy against melanoma.

A Nucleus-Targeted Nanosystem Integrated with Photodynamic Therapy and Chemotherapy.

Minimally invasive photodynamic therapy, destroying lesions with a light-activated photosensitizer, has been increasingly performed since it is highly efficiency, safe, synergistically compatible, repeatable, and minimally-invasive, with few adverse reactions. However, the most present photosensitizer or nanodrug delivery system containing a photosensitizer can target tumor cells but rarely cell nuclei. In this regard, the nucleus-targeting drug delivery system has been developed aiming impair tumor cells in an efficient and direct manner. In this study, the cationic liposome (Clip) drug delivery system integrated with low dose nucleus-targeting chemotherapeutic drug Doxorubicin (DOX) and photosensitizer AlPcS4 (Clip-AlPcS4@DOX) was synthesized. Among them, Clip was used to efficiently load drugs into cells almost at the same time, low dose DOX was used to open the channel for the materials to enter the nucleus on the premise of ensuring low cytotoxicity and then introduced photosensitizer into the nucleus, AlPcS4 photosensitizer was used to damage directly and efficiently through the photodynamic therapy (PDT) effect after entering the nucleus. In summary, a nucleus-targeting nanodrug delivery system (Clip-AlPcS4@DOX) was designed and synthesized and could be induced cell apoptosis more quickly and efficiently. Therefore, it could be a promising nucleus-targeting nanosized reagent integrating the PDT and chemotherapy for gastric therapy.

Influence of Parameters on Photodynamic Therapy of Au@TiO2-HMME Core-Shell Nanostructures.

Photodynamic therapy (PDT) is a promising tumor therapy and has been proven to be an effective, safe and minimally invasive technique. Hematoporphyrin monomethyl ether (HMME) mediated PDT has been used in clinical treatment of port wine stain (PWS) due to its single component, high yield of singlet oxygen and short light-sensitive period. However, as an amphiphilic photosensitizer, HMME is easy to aggregate due to the presence of a hydrophobic group, which undesirably reduced its generation of singlet oxygen and bioavailability. In this study, we synthesized the stable conjugate of Au@TiO2 core-shell nanostructure with HMME, and the influence of different factors on PTD efficiency were studied. The results showed that the nanostructure had higher PTD efficiency for KB cells than that of HMME. The irradiation wavelength, gold nanoparticle shape and the shell thickness are all important factors for KB cell PDT.

Gold-seaurchin based immunomodulator enabling photothermal intervention and αCD16 transfection to boost NK cell adoptive immunotherapy.

Despite huge potentials of NK cells in adoptive cell therapy (ACT), formidable physical barriers of the tumor tissue and deficiency of recognizing signals on tumor cells severely prevent NK cell infiltrating, activating and killing performances. Herein, a nano-immunomodulator AuNSP@αCD16 (CD16 antibody encoding plasmid) is explored to remodel the tumor microenvironment (TME) for improving the antitumor effects of adoptive NK cells. The as-prepared AuNSP, with a seaurchin-like gold core and a cationic polymer shell, exhibited a high gene transfection efficiency and a stable NIR-II photothermal capacity. The AuNSP could trigger mild photothermal intervention to partly destroy tumors and collapse the dense physical barriers, making a permeable TME for NK cell infiltration. What's more, the AuNSP could achieve αCD16 gene transfection to modify tumor surface with CD16 antibody, marking a unique structure on tumor cells for NK cell recognition and then lead to strong NK cell activation by CD16-mediated antibody-dependent cellular cytotoxicity (ADCC). As expected, the designed AuNSP@αCD16 induced an immune-favorable TME for NK cell performing killing functions against solid tumors, increasing the release of cytolytic granules and proinflammatory cytokines, which ultimately achieved a robustly boosted NK cell-based immunotherapy. Hence, the AuNSP@αCD16-mediated TME reconstituting strategy provides a substantial perspective for NK-based ACT on solid tumors. STATEMENT OF SIGNIFICANCE: In adoptive cell therapy (ACT), natural killer (NK) cells exhibit greater off-the-shelf utility and improved safety comparing with T cells, but the efficacy of NK cell therapy is severely compromised by formidable physical barriers of the tumor tissue and deficiency of NK cell recognizing signals on tumor cells. Herein, a nano-immunomodulator AuNSP@αCD16, with the abilities of inducing mild photothermal intervention and modifying the tumor cell surface with αCD16, is explored to reconstruct an infiltration-favorable and activation-facilitating tumor microenvironment for NK cells to perform killing functions. Such a simple and safe strategy is believed as a very promising candidate for future NK-based ACT.

Influence of Parameters on the Death Pathway of Gastric Cells Induced by Gold Nanosphere Mediated Phototherapy.

Gold nanosphere (AuS) is a nanosized particle with inert, biocompatible, easily modified surface functionalization and adequate cell penetration ability. Photothermal, photochemical, and vapor effects of AuS could be activated by irradiating with nanosecond laser to cause cell death. Hence, AuS-mediated phototherapy irradiated with nanosecond laser is a promising and minimally-invasive treatment method for cancer therapy. However, various effects require different parameters to be activated. At present, few studies have reported on the influence of parameters of AuS inducing cell death under nanosecond laser irradiation. This makes it very challenging to optimize gold-nanoparticle-mediated specific or synergistic anti-cancer therapy. In this study, we revealed the main parameters and threshold values for AuS-mediated gastric cancer phototherapy with nanosecond pulsed laser irradiation, evaluated the pathway of induced cell death, and discussed the roles of photothermal, photochemical and vapor effects which can induce the cell death. The results showed that AuS-mediated phototherapy activated with nanosecond pulsed laser is an effective method for gastric therapy, mainly based on the photochemical effect. Prolonging the incubation time could decrease the irradiation dose, increase ROS-mediated photothermal effect and vapor effect, and then quickly induce cell death to improve security.

Red Blood Cell-Mimic Nanocatalyst Triggering Radical Storm to Augment Cancer Immunotherapy.

Red blood cells (RBCs) have recently emerged as promosing candidates for cancer treatment in terms of relieving tumor hypoxia and inducing oxidative damage against cancer cells, but they are still far from satisfactory due to their limited oxygen transport and reactive oxygen species generation rate in tumor tissue. Herein, artificial RBCs (designated FTP@RBCM) with radical storm production ability were developed for oncotherapy through multidimensional reactivity pathways of Fe-protoporphyrin-based hybrid metal-organic frameworks (FTPs, as the core), including photodynamic/chemodynamic-like, catalase-like and glutathione peroxidase-like activities. Meanwhile, owing to the advantages of long circulation abilities of RBCs provided by their cell membranes (RBCMs), FTP with a surface coated with RBCMs (FTP@RBCM) could enormously accumulate at tumor site to achieve remarkably enhanced therapeutic efficiency. Intriguingly, this ROS-mediated dynamic therapy was demonstrated to induce acute local inflammation and high immunogenic cancer death, which evoked a systemic antitumor immune response when combined with the newly identified T cell immunoglobulin and mucin-containing molecule 3 (Tim-3) checkpoint blockade, leading to not only effective elimination of primary tumors but also an abscopal effect of growth suppression of distant tumors. Therefore, such RBC-mimic nanocatalysts with multidimensional catalytic capacities might provide a promising new insight into synergistic cancer treatment.

Nanoliposomes co-encapsulating Ce6 and SB3CT against the proliferation and metastasis of melanoma with the integration of photodynamic therapy and NKG2D-related immunotherapy on A375 cells.

Purpose. To overcome the insufficiency of conventional photodynamic therapy (PDT) for treating metastatic melanoma, the combination of smart nanoparticles and PDT with immunotherapy was used to achieve a higher efficiency by accumulating more photosensitizers in tumor areas and triggering stronger immune responses against tumors after PDT.Methods. In this study, we designed a nanoliposome co-encapsulation of chlorin E6 (Ce6) and SB-3CT to realize significant antitumoral proliferation and metastasis efficacy after laser irradiation in A375 cells. The morphology, size distribution, and loading efficiency of Ce6-SB3CT@Liposome (Lip-SC) were characterized. The reactive oxygen species (ROS) generation and cytotoxicity were evaluated in A375 cells, and the mechanisms of natural killer (NK) cell-mediated killing were assessed.Results. Lip-SC showed good stability and was well-dispersed with a diameter of approximately 140 nm in phosphate-buffered saline. The nanoliposomes could accumulate in tumor areas and induce apoptosis in cancer cells upon 660 nm light irradiation, which could trigger an immune response and induce the expression of NK group 2 member D (NKG2D) ligands. The subsequently released SB-3CT could further activate NK cells effectively and strengthen the immune system by inhibiting the shedding of soluble NKG2D ligands.Discussion. Taken together, the synergistic effects of SB-3CT on nanoliposomes for Ce6-mediated PDT were analyzed in detail to provide a new platform for future anti-melanoma treatment.

Emerging nanotechnological strategies to reshape tumor microenvironment for enhanced therapeutic outcomes of cancer immunotherapy.

Immunotherapy has emerged as a novel cancer treatment over the last decade, however, efficacious responses to mono-immunotherapy have only been achieved in a relatively small portion of patients whereas combinational immunotherapies often lead to concurrent side effects. It has been proved that the tumor microenvironment (TME) is responsible for tumor immune escape and the ultimate treatment failure. Recently, there has been remarkable progress in both the understanding of the TME and the applications of nanotechnological strategies, and reviewing the emerging immune-regulatory nanosystems may provide valuable information for specifically modulating the TME at different immune stages. In this review, we focus on comprehending the recently-proposed T-cell-based tumor classification and identifying the most promising targets for different tumor phenotypes, and then summarizing the nanotechnological strategies to best target corresponding immune-related factors. For future precise personalized immunotherapy, tailor-made TME modulation strategies conducted by well-designed nanosystems to alleviate the suppressive TME and then promote anti-tumor immune responses will significantly benefit the clinical outcomes of cancer patients.

Integration of pre-surgical blood test results predict microvascular invasion risk in hepatocellular carcinoma.

Microvascular invasion (MVI) is one of the most important factors leading to poor prognosis for hepatocellular carcinoma (HCC) patients, and detection of MVI prior to surgical operation could great benefit patient's prognosis and survival. Since it is still lacking effective non-invasive strategy for MVI detection before surgery, novel MVI determination approaches were in urgent need. In this study, complete blood count, blood test and AFP test results are utilized to perform preoperative prediction of MVI based on a novel interpretable deep learning method to quantify the risk of MVI. The proposed method termed as "Interpretation based Risk Prediction" can estimate the MVI risk precisely and achieve better performance compared with the state-of-art MVI risk estimation methods with concordance indexes of 0.9341 and 0.9052 on the training cohort and the independent validation cohort, respectively. Moreover, further analyses of the model outputs demonstrate that the quantified risk of MVI from our model could serve as an independent preoperative risk factor for both recurrence-free survival and overall survival of HCC patients. Thus, our model showed great potential in quantification of MVI risk and prediction of prognosis for HCC patients.

A benzothiazole-based near-infrared fluorescent probe for sensing SO2 derivatives and viscosity in HeLa cells.

The unbalanced metabolism of sulfur dioxide can cause various diseases, such as neurological disorders and lung cancer. Until now, some researches revealed that the normal function of lysosomes would be disrupted by its abnormal viscosity. As a signal molecule, sulfur dioxide (SO2) plays an important role in lysosome metabolism. However, the connection of metabolism between the SO2 and viscosity in lysosomes is still unknown. Herein, we developed a benzothiazole-based near-infrared (NIR) fluorescent probe (Triph-SZ), which can monitor the SO2 derivatives and respond to the change of viscosity in lysosomes through two-photon imaging. Triph-SZ present high sensitivity and selectivity fluorescence response with the addition of SO2 derivatives based on the nucleophilic addition, and it also exhibits a sensitive fluorescence enhancement to environmental viscosity, which allows Triph-SZ to be employed to monitor the level of HSO3- and viscosity changes in lysosomes by the two-photon fluorescence lifetime imaging microscopy.

Localized NIR-II photo-immunotherapy through the combination of photothermal ablation and in situ generated interleukin-12 cytokine for efficiently eliminating primary and abscopal tumors.

Recently, photothermal therapy (PTT) in the second near-infrared (NIR-II) biowindow has emerged as a promising treatment modality; however, its therapeutic outcomes are still limited by heterogeneous heat distribution and insufficient control of metastatic lesions. Tremendous efforts have been made to overcome the PTT's shortcomings by combining PTT with immunotherapy, but unfortunately current strategies still suffer from low response rates, primary/acquired resistance or severe immune-related adverse events. Herein, a novel photothermal agent and gene co-delivery nanoparticle (CSP), with CuS inside the SiO2 pore channels and PDMAEMA polycation on the outside of SiO2 surface, is explored for tumor localized NIR-II PTT and in situ immunotherapy through local generation of IL-12 cytokine. The resulting CSP integrated with the plasmid encoding IL-12 gene (CSP@IL-12) exhibited good gene transfection efficiency, outstanding NIR-II PTT effect and excellent therapeutic outcomes both in vitro and in vivo. Meanwhile, such an in situ joint therapy modality could significantly induce systemic immune responses including promoting DC maturation, CD8+ T cell proliferation and infiltration to efficiently eliminate possible metastatic lesions through abscopal effects. Hence, this creative combinational strategy of NIR-II PTT and IL-12 cytokine therapy might provide a more efficient, controllable and safer alternative strategy for future photo-immunotherapy.

X-ray-Induced Cherenkov Optical Triggering of Caged Doxorubicin Released to the Nucleus for Chemoradiation Activation.

Concurrent chemoradiotherapy is used for advanced cancers, but the chemotherapy is dose limited by normal tissue toxicity. Localized X-ray activation of chemotherapy could overcome this, as studied here, with release from self-assembled nanomicelles (NMs) created from copolymers loaded with doxorubicin (DOX) having a photocleavable o-nitrobenzyl ester (o-Ne) group. The micelles demonstrated release of DOX from X-ray-induced Cherenkov light and conversion from a caged hydrophobic form to hydrophilic DOX, which achieves nuclear localization. Folate on the exterior of the NMs directed them for effective intracellular uptake prior to irradiation. Irradiation with 8 Gy released the DOX, which then entered the cell nucleus, providing near-complete in vivo tumor eradication and negligible off-target organ damage. Micelles were assembled from molecular component materials that are commonly in human use. This study realizes triple targeting in chemoradiation with potential for cell-receptor-mediated uptake, localized radiotherapy activation, and nuclear relocalization, all leading to limited off-target toxicity.

Time-gated luminescence imaging for background free in vivo tracking of single circulating tumor cells.

Fluorescence imaging is severely limited by the background and autofluorescence of tissues for in vivo detection of circulating tumor cells (CTCs). Time-gated luminescence (TGL) imaging, in combination with luminescent probes that possess hundreds of microsecond emission lifetimes, can be used to effectively suppress this background, which has predominantly nanosecond lifetimes. This Letter demonstrates the feasibility of TGL imaging using luminescent probes for the in vivo real time imaging and tracking of single CTCs circulating freely in the blood vessels with higher accuracy given by substantially higher signal-to-noise ratio. The luminescent probe used in this Letter was a commercial Eu3+ chelate (EuC) nanosphere with a super-long lifetime of near 800 µs, which enabled TGL imaging to achieve background-free detection with ∼5 times higher SNR versus steady state. Phantom and in vivo mouse studies indicated that EuC labeled tumor cells moving in medium or bloodstream at the speed of 1-2 mm/s could be captured in real time.