Prevalence and risk factors of sexual dysfunction in female participants with rheumatoid arthritis: a systematic review and meta-analysis.

BACKGROUND: The prevalence and risk factors of female sexual dysfunction (FSD) in female participants with rheumatoid arthritis (RA) were reported with inconsistent results. However, no systematic review and meta-analysis of pooled data provide reliable estimates of FSD prevalence in female participants with RA. AIM: To investigate the global prevalence and risk factors of FSD in female participants with RA and to analyze the association between FSD risk and RA. METHODS: The study search of this systematic review and meta-analysis was conducted through PubMed, Cochrane Library, Web of Science, and Embase from the inception date to December 10, 2023. Random effects meta-analysis was performed to derive the pooled prevalence. Q and I2 tests were used to analyze heterogeneity among the studies. Subgroup analyses and meta-regression were used to detect the sources of heterogeneity. OUTCOMES: The pooled prevalence of FSD in female participants with RA was calculated, and odds ratios (ORs) and 95% CIs were used to assess the strength of the association between FSD-related risk factors and RA. RESULTS: A total of 13 studies were included in our analysis, involving 2327 participants. The pooled prevalence of FSD in female participants with RA was 49.1% (95% CI, 38.2%-60%). The participants with RA had a higher risk of FSD than healthy controls (OR, 3.10; 95% CI, 1.74-5.53). The significant risk factors of FSD in female participants with RA were depression status (OR, 1.42; 95% CI, 0.88-2.29) and menopause (OR, 5.46; 95% CI, 2.04-14.63). CLINICAL IMPLICATIONS: Female participants with RA had a significantly increased prevalence of FSD, indicating that sexual function in female participants with RA should be concerned by clinicians. STRENGTHS AND LIMITATIONS: The strength of this study is that it is the first meta-analysis to assess the global prevalence and risk factors of FSD in female participants with RA. A limitation is that the results, after the articles were pooled, showed significant heterogeneity and publication bias. CONCLUSIONS: The present systematic review and meta-analysis revealed that the overall prevalence of FSD in female participants with RA was 49.1%, indicating a significant association between FSD risk and RA among females. Moreover, menopause and depression status were significantly associated with FSD in female participants with RA.

Molecular Imaging of Renin Activity using Fluorogenic Nanoprobes for Precision Antihypertensive Therapy.

Life-threatening hypertension remains inadequately controlled in clinics due to its heterogenous renin levels. Rapid stratification of hypertension through renin analysis is crucial for effective personalized treatment, yet an ultrasensitive detection approach is currently lacking. Here, we report activatable renin nanoprobes (ARNs) for non-invasive and ultrasensitive profiling of renin activity and guiding antihypertensive treatment decision through near-infrared fluorescence (NIRF) in vivo imaging and in vitro urinalysis. ARNs are intrinsically non-fluorescent due to NIRF reporter connected to a gold nanocluster through a renin-responsive peptide. In hyperreninemia mouse models, ARNs specifically react with renin to liberate the renal clearable NIRF reporter for accurate renin detection that outperforms the gold standard radioimmunoassay. Such specific and sensitive detection also enables imaging-based high-throughput screening of antihypertensive drugs. In hypertensive rat models, ARNs enable ultrasensitive detection of both plasma and urinary renin, facilitating renin-guided precision treatment and significantly improving hypertension control rate (90% versus 58%). Our nanoprobe platform holds great potential for assisting clinicians in rapidly and accurately classifying hypertensive patients and improving outcomes through tailored treatment selection.

Prediction models for urinary incontinence after robotic-assisted laparoscopic radical prostatectomy: a systematic review.

Even though robotic-assisted laparoscopic radical prostatectomy (RARP) is superior to open surgery in reducing postoperative complications, 6-20% of patients still experience urinary incontinence (UI) after surgery. Therefore, many researchers have established predictive models for UI occurrence after RARP, but the predictive performance of these models is inconsistent. This study aims to systematically review and critically evaluate the published prediction models of UI risk for patients after RARP. We conducted a comprehensive literature search in the databases of PubMed, Cochrane Library, Web of Science, and Embase. Literature published from inception to March 20, 2024, which reported the development and/or validation of clinical prediction models for the occurrence of UI after RARP. We identified seven studies with eight models that met our inclusion criteria. Most of the studies used logistic regression models to predict the occurrence of UI after RARP. The most common predictors included age, body mass index, and nerve sparing procedure. The model performance ranged from poor to good, with the area under the receiver operating characteristic curves ranging from 0.64 to 0.98 in studies. All the studies have a high risk of bias. Despite their potential for predicting UI after RARP, clinical prediction models are restricted by their limited accuracy and high risk of bias. In the future, the study design should be improved, the potential predictors should be considered from larger and representative samples comprehensively, and high-quality risk prediction models should be established. And externally validating models performance to enhance their clinical accuracy and applicability.

Causal relationship between prostatic diseases and prostate cancer: a mendelian randomization study.

BACKGROUND: Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are unclear. METHODS: We assessed the causal relationship between prostatitis or BPH and PCa using a two-sample Mendelian randomization (MR) approach. The data utilized in this study were sourced from genome-wide association study. The association of genetic variants from cohorts of prostatitis or BPH and PCa patients was determined using inverse-variance weighted and MR Egger regression techniques. The direction of chance was determined using independent genetic variants with genome-wide significance (P < 5 × 10-6). The accuracy of the results was confirmed using sensitivity analyses. RESULTS: MR analysis showed that BPH had a significant causal effect on PCa (Odds Ratio = 1.209, 95% Confidence Interval: 0.098-0.281, P = 5.079 × 10- 5) while prostatitis had no significant causal effect on PCa (P > 0.05). Additionally, the pleiotropic test and leave-one-out analysis showed the two-sample MR analyses were valid and reliable. CONCLUSIONS: This MR study supports that BPH has a positive causal effect on PCa, while genetically predicted prostatitis has no causal effect on PCa. Nonetheless, further studies should explore the underlying biochemical mechanism and potential therapeutic targets for the prevention of these diseases.

A ß-Galactosidase-Activated Fluorogenic Reporter for the Detection of Gastric Cancer In Vivo and in Urine.

Although gastric cancer (GC) is one of the most frequent malignant tumors in the digestive tract with high morbidity and mortality, it remains a diagnostic dilemma due to its reliance on invasive biopsy or insensitive assays. Herein, we report a fluorescent gastric cancer reporter (FGCR) with activatable near-infrared fluorescence (NIRF) signals and high renal-clearance efficiency for the detection of orthotopic GC in a murine model via real-time imaging and remote urinalysis. In the presence of gastric-tumor-associated ß-galactosidase (ß-Gal), FGCR can be fluorescently activated for in vivo NIRF imaging. Relying on its high renal-clearance efficiency (∼95% ID), it can be rapidly excreted through kidneys to urine for the ultrasensitive detection of tumors with a diameter down to ∼2.1 mm and for assessing the prognosis of oxaliplatin-based chemotherapy. This study not only provides a new approach for noninvasive auxiliary diagnosis and prognosis of GC but also provides guidelines for the development of fluorescence probes for cancer diagnosis.

Engineering Cyanine- and Hemicyanine-Based Probes for Optical Imaging of Kidney Diseases.

Molecular optical probes play pivotal roles in in vivo imaging of biomarkers associated to kidney diseases. Relying on structural tunability and high fluorescence quantum yields, versatile optical probes have been constructed on cyanine or hemicyanine-based scaffold in recent years. This review summaries the recent progress on the development of optical probes for imaging of kidney diseases, particularly through near-infrared fluorescence, chemiluminescence and photoacoustic imaging modalities. The chemical design and sensing mechanisms are discussed along with applications in the detection of renal cell carcinoma and acute kidney injury. This progress provides insights and directions for the development of next generation kidney-targeted probes and for pushing their further applications in preclinical and clinical research.

The characteristics of sexual behavior in blind men in Ganzhou, China: A cross-sectional study.

Visual stimuli play key roles in influencing men sexual behavior. However, few studies have explored the sexual behavior of blind men. To provide more information about blind men for the study of andrology by surveying the characteristics of their current sexual behavior. A questionnaire-based cross-sectional study design was performed. The questionnaire contained questions regarding demographic characteristics of participants, access to sexual knowledge, perception of the sexual partners' beauty, and sexual arousal. Blind men were interviewed face-to-face by the trained investigator. Complete questionnaires were collected from 54 participants, with an average age of 40.57 ±â€…9.80 years old. Eye diseases were the most frequent cause of blindness. In terms of sexual orientation, all participants were heterosexual. Notably, 90.7% of the participants reported to have had a sexual experience. Among those who had engaged in sexual behavior, 93.6% experienced sexual pleasure and 69.4% had a normal erectile function. Overall, 16.7% of the participants received sex education. The participants obtained sexual knowledge mainly through sounds from mobile phones, peer-to-peer communication, sounds of television and radio. Voice was the most frequent perception of the sexual partners' beauty, followed by figure, skin, and body fragrance. In terms of stimuli of sexual arousal, tactile sensation and auditory sensation in that order were the most frequent stimuli of sexual arousal. Stimuli of sexual arousal in blind men are mainly mediated by sound and touch. Blind men understand their sexual partners' beauty through auditory, tactile, and olfactory sensations. Blind men in Ganzhou lack formal and systematic sex education.

Long non-coding RNA H19 mediates the miR-29b/transforming growth factor-ß1/Drosophila mothers against decapentaplegic 3 signalling pathway to promote bladder fibrosis in diabetic rats.

PURPOSE: Diabetic bladder fibrosis is a common comorbidity. Altered expression of some long non-coding RNAs (LncRNAs) has been associated with bladder fibrosis. LncRNA H19 has been reported to regulate bladder cancer through miR-29b. However, the action mechanism of LncRNA H19 in bladder fibrosis is unclear. METHODS: In vitro, human bladder smooth muscle cells (HBSMCs) were cultured with transforming growth factor-ß1 (TGF-ß1) for 48 h to construct cell model of bladder fibrosis. HBSMCs were then transfected with si-LncRNA H19, si-NC, miR-29b-mimic, mimic-NC, or miR-29b-inhibitor. In vivo, Sprague-Dawley (SD) rats were given a high-sucrose-high-fat (HSHF) diet for 4 weeks and injected with streptozotocin (STZ, 50 mg/kg) to induce bladder fibrosis model in diabetic rats, followed by injection of lentiviral particles knocking down LncRNA H19 expression, empty vector, or miR-29b-inhibitor, respectively. RESULTS: LncRNA H19 was up-regulated in TGF-ß1-induced HBSMC fibrosis and STZ-induced diabetic rat bladder fibrosis, whereas miR-29b was down-regulated. si-LncRNA H19 reduced blood glucose levels and improved histopathological damage of bladder tissue in rats. In addition, si-LncRNA H19 or miR-29b-mimic increased the expression of E-cadherin, but decreased the expression of N-cadherin, vimentin, fibronectin (FN) in bladder tissues, and HBSMCs. si-LncRNA H19 reduced TGF-ß1/p-drosophila mothers against decapentaplegic 3 (Smad3) protein in HBSMCs and in rat bladder tissues, while miR-29b-inhibitor reversed the effect of si-LncRNA H19. CONCLUSION: This study indicated that LncRNA H19 may inhibit bladder fibrosis in diabetic rats by targeting miR-29b via the TGF-ß1/Smad3 signalling pathway.

Predictive value of controlling nutritional status score for prostate cancer diagnosis.

Objective: This study aims to explore the predictive value of the Controlling Nutritional Status (CONUT) score for prostate cancer (PCa) diagnosis. Methods: The data of 114 patients who underwent prostate needle biopsies from June 2020 to December 2022 were retrospectively analyzed. The relationship between CONUT score and various clinical factors as well as PCa diagnosis was evaluated. Results: The pathological results classified patients into the PCa (n = 38) and non-PCa (n = 76) groups. Compared with the non-PCa group, the PCa group exhibited statistically significant differences in age, prostate-specific antigen (PSA), PSA density (PSAD), the proportion of PI-RADS ≥ 3 in mpMRI, and the CONUT score, prostate volume, lymphocyte count, and total cholesterol concentration (p < 0.05). ROC curve analyses indicated the diagnostic accuracy as follows: age (AUC = 0.709), prostate volume (AUC = 0.652), PSA (AUC = 0.689), PSAD (AUC = 0.76), PI-RADS ≥ 3 in mpMRI (AUC = 0.846), and CONUT score (AUC = 0.687). When CONUT score was combined with PSA and PSAD, AUC increased to 0.784. The AUC of CONUT score combined with PSA, PSAD, and mpMRI was 0.881, indicates a higher diagnostic value. Based on the optimal cut-off value of CONUT score, compared with the low CONUT score group, the high CONUT score group has a higher positive rate of PCa diagnosis (p < 0.05). Conclusion: CONUT score is an excellent auxiliary index for PCa diagnosis in addition to the commonly used PSA, PSAD, and mpMRI in clinical practice. Further prospective trials with a larger sample size are warranted to confirm the present study findings.

Molecular Engineering of Activatable NIR-II Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Inflammatory Bowel Disease.

Molecular imaging in the second near-infrared window (NIR-II) provides high-fidelity visualization of biopathological events in deep tissue. However, most NIR-II probes produce "always-on" output and demonstrate poor signal specificity toward biomarkers. Herein, we report a series of hemicyanine reporters (HBCs) with tunable emission to NIR-II window (715-1188 nm) and structurally amenable to constructing activatable probes. Such manipulation of emission wavelengths relies on rational molecular engineering by integrating benz[c,d]indolium, benzo[b]xanthonium, and thiophene moieties to a conventional hemicyanine skeleton. In particular, HBC4 and HBC5 possess bright and record long emission over 1050 nm, enabling improved tissue penetration depth and superior signal to background ratio for intestinal tract mapping than NIR-I fluorophore HC1. An activatable inflammatory reporter (AIR-PE) is further constructed for pH-triggered site-specific release in colon. Due to minimized background interference, oral gavage of AIR-PE allows clear delineation of irritated intestines and assessment of therapeutic responses in a mouse model of inflammatory bowel disease (IBD) through real-time NIRF-II imaging. Benefiting from its high fecal clearance efficiency (>90%), AIR-PE can also detect IBD and evaluate the effectiveness of colitis treatments via in vitro optical fecalysis, which outperforms typical clinical assays including fecal occult blood testing and histological examination. This study thus presents NIR-II molecular scaffolds that are not only applicable to developing versatile activatable probes for early diagnosis and prognostic monitoring of deeply seated diseases but also hold promise for future clinical translations.

Renal-clearable nanoprobes for optical imaging and early diagnosis of diseases.

Optical imaging has played an indispensable role in clinical diagnostics and fundamental biomedical research due to its high sensitivity, high spatiotemporal resolution, cost-effectiveness, and easy accessibility. However, the issues of light scattering and low tissue penetration make them effective only for superficial imaging. To overcome these issues, renal-clearable optical nanoprobes have recently emerged, which are activated by abnormal disease-associated biomarkers and initiate a pharmacokinetic switch by undergoing degradation and eventually releasing signal reporters into urine, for simple imaging and sensitive optical in vitro urinalysis. In this review, we focus on the advancements of renal-clearable organic nanoprobes for optical imaging and remote urinalysis. The versatile design strategies of these nanoprobes are discussed along with their sensing mechanisms toward biomolecules of interest as well as their unique biological applications. Finally, challenges and perspectives are discussed to further advance the next-generation renal-clearable nanoprobes for in vivo imaging and in vitro urinalysis.

Minimally Invasive Surgical Therapies for Ureteral Polyps: A Systematic Review.

Background: Ureteral polyps are rare benign ureteral tumor. No guideline recommends that open or minimally invasive surgery is best for treating ureteral polyps. This article aims to provide a comprehensive review of the minimally invasive techniques currently available for treating ureteral polyps. Materials and Methods: We performed a comprehensive search of articles published in PubMed, using the keywords "ureteral" and "polyp," or "polyps." Results: A total of 275 studies were obtained from the literature search but 96 articles were excluded. Conclusions: Several minimally invasive approaches were developed with the advancement of medical technology, including endoscopic, laparoscopic, and robotic approaches; however, the best surgical technique was yet to be decided. Due to the advantages and disadvantages of these approaches, the best surgical approach should be tailored to each patient's needs and the surgeon's preferences and experience.

Prevalence of overactive bladder in Chinese women: A systematic review and meta-analysis.

BACKGROUND: Overactive bladder (OAB) is a significant public health issue that adversely affects the quality of life of patients and imposes a significant socioeconomic burden, with varying prevalence rates across study populations in Chinese women. A systematic review and meta-analysis were conducted to estimate the prevalence of OAB in Chinese women. METHODS: Relevant published articles on the prevalence of OAB in Chinese women were searched through July 21, 2022, using PubMed, EMbase, The Cochrane Library, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), WanFang Data, and VIP databases. After the independent screening of articles, data extraction, and quality assessment of included studies by two investigators, a meta-analysis was performed using Stata 16.0 software, and the prevalence was determined using a random-effects model. To identify potential sources of heterogeneity, subgroup analyses were conducted with subgroup categories including age, Body Mass Index (BMI), region, and survey year. Publication bias was assessed by visually examining the funnel plot and Egger's test. RESULTS: Twenty studies were included in this meta-analysis. The results of the random-effects model indicated that the prevalence of OAB in Chinese women was 14% (95% Confidence Interval: 9%-18%). The prevalence increased significantly in the past decade (from 8% in pre-2006 to 18% in 2016-2021). A prevalence (18%) was observed among women aged 31-40 compared with other age groups. The BMI range of 24-27.9 (18%) was higher than the other groups. Additionally, the prevalence of this BMI range was comparatively higher in North China and Southwest China (21%) than in Central China and East China. In addition, publication bias was observed. CONCLUSIONS: OAB incidence has increased in Chinese women over the last two decades, affecting more than 20% of women aged 31-40 years and above. With the increasing prevalence of OAB, greater emphasis has been placed on implementing preventative and control measures.

Tailored Zwitterionic Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Acute Renal Failure.

Drug-induced renal failure (DIRF) poses a serious medical complication with high mortality risk. However, early diagnosis or prognosis of DIRF remain challenging, as current methods rely on detecting late-stage biomarkers. Herein we present a library of zwitterionic unimolecular hemicyanines (ZCs) available for constructing activatable reporters to detect DIRF since its initial stage. Zwitterionic properties of these probes are achieved through interspersedly integrating alkyl sulfonates and quaternary ammonium cations onto hemicyanine skeleton, which result in record low plasma protein binding (<5 %) and remarkable renal clearance efficiencies (≈96 %). An activatable reporter ZCRR is further developed by masking the optimal candidate ZC6 with a tetrapeptide specifically cleavable by caspase-8, an initiating indicator of apoptosis. In living mice with cisplatin-induced DIRF, systematically administered ZCRR efficiently accumulates in kidneys and responds to elevated caspase-8 for near-infrared fluorescence signals 'turn-on', enabling sensitive detection of intrarenal apoptosis 60 h earlier than clinical methods, and precise evaluation of apoptosis remediation effects by different medications on DIRF mice. As it's urinary excretable, ZCRR also allows for remote detection of DIRF and predicting renoprotective efficacy through in vitro optical urinalysis. This study thus presents unimolecular renal clearable scaffolds that are applicable to developing versatile activatable reporters for renal diseases management.

Transurethral 1470 nm diode laser vaporization versus plasma kinetic enucleation of the prostate for the treatment of benign prostatic hyperplasia: A retrospective study.

To compare the efficacy, safety, and complications of transurethral 1470 nm diode laser vaporization and plasma kinetic enucleation of prostate (PKEP) in benign prostatic hyperplasia treatment. A retrospective matched-paired comparison of patients treated using transurethral 1470 nm diode laser vaporization (n = 40) or PKEP (n = 40) was conducted. Baseline characteristics, preoperative data, and postoperative outcomes at the 24-month follow-up of the patients were recorded. The present study found no significant preoperative differences between the 2 treatment groups. Compared with PKEP, 1470 nm diode laser vaporization had a significantly shorter operation time and less intraoperative blood loss, but there were no marked differences between the 2 groups in terms of postoperative bladder irrigation time, catheterization time, and hospital stay. Moreover, at the 24-month follow-up postoperatively, there were no marked differences in the International Prostatic Symptomatic Score (IPSS), quality of life (QOL), maximum urinary flow rate (Qmax), and post-void residual urine volume (PVR) between the 2 groups. IPSS, QOL, Qmax, and PVR had improved significantly compared to preoperative assessment at 24-month follow-up in both groups and there was no significant difference in the variation of IPSS, QOL, Qmax and PVR before and after the operation. Furthermore, complications were comparable between the 2 treatment groups. Transurethral 1470 nm diode laser vaporization and PKEP are effective strategies in the treatment of benign prostatic hyperplasia. However, 1470 nm diode laser vaporization offers advantages over PKEP in terms of shortening operation time and reducing intraoperative bleeding. Nonetheless, further research with a larger number of patients and long-term follow-up is necessary to confirm and validate these findings.

Rectal prolapse in a 30-year-old bladder stone male patient: A case report.

BACKGROUND: Rectal prolapse occurs most commonly in children and middle-aged and elderly women and is relatively rare in young men and is occasionally caused by bladder stones. Severe rectal prolapse, bilateral hydronephrosis, and renal insufficiency caused by bladder stones are rare in a 30-year-old man. CASE SUMMARY: We report the case of a 30-year-old male patient with cerebral palsy who presented with a large bladder stone that resulted in severe rectal prolapse, bilateral hydronephrosis, and renal insufficiency. Following a definitive diagnosis, the bladder stone was successfully removed, and his kidney function returned to normal. We assessed the patient's nutritional status and stone composition and concluded that the main cause was malnutrition. CONCLUSION: Rectal prolapse is a rare clinical manifestation of bladder stones, particularly in young adults. Cerebral palsy patients are a vulnerable group in society because of their intellectual disabilities and communicative impairments. Accordingly, besides taking care of their daily diet, abnormal signs in their bodies should receive the doctors' attention in a timely manner.

Recurrent paratesticular giant liposarcoma: A case report and literature review.

Background: Primary paratesticular liposarcoma is rarely diagnosed among urinary tumors. In this study, through the retrospective analysis of clinical data and literature review, a case of recurrent paratesticular liposarcoma with lymph node metastasis after radical resection has been reported to explore novel strategies for the diagnosis, treatment and prognosis of this rare disease. Case summary: The present case involved a patient who was misdiagnosed as a left inguinal hernia for the first time two years ago, but was later diagnosed as mixed liposarcoma by using postoperative pathology. Currently, he is readmitted to the hospital with a recurrence of the left scrotal mass for more than 1 year. Combined with the patient's past medical history, we performed radical resection of the left inguinal and scrotal tumors and lymphadenectomy of left femoral vein. The postoperative pathology indicated that well-differentiated liposarcoma was accompanied by mucinous liposarcoma (about 20%), and lymph node metastasis of left femoral vein both of which occurred at the same time. After the operation, we recommended the patient to receive further radiation therapy, but the patient and his family refused, hence we followed up the patient closely for a long time. During the recent follow-up, the patient reported no complaints of discomfort, and no recurrence of mass in the left scrotum and groin area. Conclusion: After conducting extensive review of literature, we conclude that radical resection remains the key to treat primary paratesticular liposarcoma, while the significance of the lymph node metastasis is still unclear. The potential effects of postoperative adjuvant therapy depends on the pathological type, and hence close follow-up observation is essential.

Spontaneous Prostatic Hemorrhage in a COVID-19 Patient: A Case Report.

Hematuria occurring in patients with acute kidney injury caused by Corona Virus Disease 2019 (COVID-19) infection has been reported. However, cases of macroscopic hematuria in COVID-19 patients leading to a severe decrease in hemoglobin have not been reported heretofore. Herein, we describe the case of a 56-year-old male patient who suffered from spontaneous prostatic hemorrhage caused by thrombocytopenia and coagulation dysfunction associated with COVID-19 infection, which manifested as macroscopic hematuria, bladder blood clot tamponade and severe hemoglobin decline. Prostatic hemorrhage was diagnosed by endoscopy. There was no recurrence of macroscopic hematuria after undergoing transurethral prostate electrocoagulation for hemostasis, infusing plasma to supplement coagulation factors and taking finasteride. One month after the bleeding event, the patient's blood routine reexamination revealed that the platelet count returned to the normal value and coagulation was normal.

Activatable Semiconducting Polymer Pro-nanomodulators for Deep-Tissue Sono-immunotherapy of Orthotopic Pancreatic Cancer.

Immunotherapy has provided a promising modality for cancer treatment, while it often has the issues of limited response rates and potential off-target side effects in clinical practice. We herein report the construction of semiconducting polymer pro-nanomodulators (SPpMs) with ultrasound (US)-mediated activatable pharmacological actions for deep-tissue sono-immunotherapy of orthotopic pancreatic cancer. Such SPpMs consist of a sonodynamic semiconducting polymer backbone grafted with poly(ethylene glycol) chains linked with two immunomodulators (a programmed death-ligand 1 blocker and an indoleamine 2,3-dioxygenase inhibitor) via a singlet oxygen (1 O2 )-cleavable segment. In view of the excellent sonodynamic property of the semiconducting polymer core, SPpMs enable effective generation of 1 O2 under US treatment, even in a deep-tissue depth up to 12 cm. The generated 1 O2 not only ablates tumors via a sonodynamic effect and induces immunogenic cell death, but also destroys the 1 O2 -cleavable segments to allow in situ release of immunomodulators in tumors. This synergetic action results in boosted antitumor immune response via reversing two tumor immunosuppressive pathways. As such, SPpMs mediate deep-tissue sono-immunotherapy to completely eradicate orthotopic pancreatic cancer and effectively prevent tumor metastasis. Moreover, such an immune activation reduces the possibility of immune-related adverse events. This study thus provides a smart activatable nanoplatform for precise immunotherapy of deep-seated tumors.

Size-Transformable Superoxide-Triggered Nanoreporters for Crosstalk-Free Dual Fluorescence/Chemiluminescence Imaging and Urinalysis in Living Mice.

Chemiluminescence imaging has been recognized as a valuable tool for ultrasensitive detection of physio-pathological events through elimination of background autofluorescence. However, most chemiluminescent nanoprobes suffer from shallow imaging depths and slow clearance from living bodies, which impede their use in clinical settings. We herein report size-transformable nanoreporters (ADN1 and ADN2) that could be activated at disease site by superoxide anion (O2 ⋅- ) to trigger nanostructure disassembly into renal excretable fluorescent fragments as well as chemiluminescence turn-on for crosstalk-free duplex chemo-fluorescence imaging and in vitro urinalysis. In peritonitis mouse model, we demonstrate that the representative nanoreporter ADN1 spontaneously accumulates at the disrupted peritoneum and is cleaved by upregulated O2 ⋅- to initiate depolymerization and result in red chemiluminescence at 620 nm, enabling sensitive detection of peritonitis at least 19 h earlier than gold standard histological assays. Additionally, the incorporation of a near-infrared (NIR) dye into ADN1 results in ADN2 exhibiting intense and red-shifted chemiluminescence at ≈800 nm, which permits early detection of deeply seated diseases such as drug-induced hepatotoxicity. This study thus showcases a modular design strategy that is not only applicable to developing versatile chemiluminescent nanoprobes with switchable pharmacokinetics for early disease diagnosis, but also promising for future clinical translations.