A Tumor-Activatable Liposomal Nanoprobe for Selective Visualization of Metastatic Lymph Nodes.

The precise identification of sentinel lymph nodes (SLNs) during surgery and assessment of their benign status is crucial for accurate tumor staging and optimal treatment strategizing. Currently, a deficiency exists in non-invasive in vivo diagnostic techniques that can accurately pinpoint SLNs during surgery while simultaneously evaluating their benign status. Here, a tumor-activatable liposomal nanoprobe (nTAL) is developed, remotely loaded with clinically approved photosensitizer, methyl aminolevulinate (MAL), to noninvasively visualize the tumor metastasis lymph nodes (LNs) with precision. Benefited from the highly efficient LNs draining of nanosized liposome and tumor cell-specific transformation of the non-fluorescent MAL to fluorescent protoporphyrin IX (PPIX), nTAL succeeded in targeting the SLNs and differentiated the metastatic from the benign ones with a positive correlation between PPIX generation and tumor cell infiltration in LNs. Moreover, the nTAL technology is capable of probing the early metastatic stage with a primary tumor size of 50 mm3. This study provides a new strategy for intraoperative visualization of real-time sentinel node dissection.

Insights into left-right asymmetric development of chicken ovary at the single-cell level.

Avian ovaries develop asymmetrically apart from prey birds, with only the left ovary growing more towards functional organs. Here, we analyze over 135,000 cells from chick's left and right ovaries at six distinct embryonic developmental stages utilizing single-cell transcriptome sequencing. We delineate gene expression patterns across 15 cell types within these embryo ovaries, revealing side-specific development. The left ovaries exhibit cortex cells, zygotene germ cells, and transcriptional changes unique to the left side. Differential gene expression analysis further identifies specific markers and pathways active in these cell types, highlighting the asymmetry in ovarian development. A fine-scale analysis of the germ cell meiotic transcriptome reveals seven distinct clusters with gene expression patterns specific to various meiotic stages. The study also identifies signaling pathways and intercellular communications, particularly between pre-granulosa and germ cells. Spatial transcriptome analysis shows the asymmetry, demonstrating cortex cells exclusively in the left ovary, modulating neighboring cell types through putative secreted signaling molecules. Overall, this single-cell analysis provides insights into the molecular mechanisms of the asymmetric development of avian ovaries, particularly the significant role of cortex cells in the left ovary.

Effects of low-intensity pulsed ultrasound on the microorganisms of expressed prostatic secretion in patients with IIIB prostatitis.

To detect and analyze the changes of microorganisms in expressed prostatic secretion (EPS) of patients with IIIB prostatitis before and after low-intensity pulsed ultrasound (LIPUS) treatment, and to explore the mechanism of LIPUS in the treatment of chronic prostatitis (CP). 25 patients (study power was estimated using a Dirichlet-multinomial approach and reached 96.5% at α = 0.05 using a sample size of 25) with IIIB prostatitis who were effective in LIPUS treatment were divided into two groups before and after LIPUS treatment. High throughput second-generation sequencing technique was used to detect and analyze the relative abundance of bacterial 16 s ribosomal variable regions in EPS before and after treatment. The data were analyzed by bioinformatics software and database, and differences with P < 0.05 were considered statistically significant. Beta diversity analysis showed that there was a significant difference between groups (P = 0.046). LEfSe detected four kinds of characteristic microorganisms in the EPS of patients with IIIB prostatitis before and after LIPUS treatment. After multiple comparisons among groups by DESeq2 method, six different microorganisms were found. LIPUS may improve patients' clinical symptoms by changing the flora structure of EPS, stabilizing and affecting resident bacteria or opportunistic pathogens.

Effects of Transportation on Blood Indices, Oxidative Stress, Rumen Fermentation Parameters and Rumen Microbiota in Goats.

The objective of this experiment was to delve into the impacts of transportation on goats. Sixteen healthy goats were selected as experimental animals; these goats were transported at a speed ranging from 35 to 45 km/h for 20 h. The changes in the physiological indexes, blood physiological indexes, biochemical indexes, rumen fermentation indexes, and rumen microbial structure composition of goats before and after transportation were measured. The results showed that after transportation, the contents of IgM, IgA, IgG, and Thyroxine decreased very significantly, while the contents of propionic acid, Hemoglobin and Epinephrine significantly increased, and the contents of VFA, acetic acid, butyric acid, isobutyric acid, isovaleric acid, LPS, IL-1ß, IL-6, TNF-α, Major Acute Phase Protein, protein carbonyl, and cortisol increased very significantly. There was no significant difference in α-diversity and ß-diversity, and the relative abundance of rumen microorganisms was not significantly different at either phylum or genus levels. The experimental findings revealed that continuous transportation for a duration of 20 h can induce a severe stress response in goats, leading to compromised immune function, diminished antioxidant capacity, escalated inflammatory response, and altered rumen fermentation indices. However, the experiment did not reveal any significant impact on the structure and composition of the rumen microbiota.

Apatinib and gamabufotalin co-loaded lipid/Prussian blue nanoparticles for synergistic therapy to gastric cancer with metastasis.

Due to the non-targeted release and low solubility of anti-gastric cancer agent, apatinib (Apa), a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects. In order to avoid these drawbacks, lipid-film-coated Prussian blue nanoparticles (PB NPs) with hyaluronan (HA) modification was used for Apa loading to improve its solubility and targeting ability. Furthermore, anti-tumor compound of gamabufotalin (CS-6) was selected as a partner of Apa with reducing dosage for combinational gastric therapy. Thus, HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue. In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor (VEGFR) and matrix metalloproteinase-9 (MMP-9). In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects. In summary, we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer (GC) therapy.

Intraoperative intravenous versus periarticular injection of glucocorticoids in improving clinical outcomes after total knee arthroplasty: A prospective, randomized and controlled study.

BACKGROUND: Glucocorticoids have been widely used in perioperative period for postoperative pain relief after total knee arthroplasty (TKA). However, the optimal administration protocols of glucocorticoids remain controversial. This study aims to compare the efficacy of glucocorticoids between intravenous and periarticular injection on clinical outcomes. METHODS: A total of 114 patients were randomly assigned to intravenous (IV) group (n = 57) and periarticular injection (PI) group (n = 57). The IV group received 10 mg dexamethasone intravenously and the PI group received periarticular injection of 10 mg dexamethasone during the procedure. The clinical outcomes were assessed using visual analogue scale (VAS), knee society score (KSS), range of motion (ROM), knee swelling, inflammation markers and complications after TKA. RESULTS: The VAS score during walking at 2nd day postoperatively was lower in the PI group compared with the IV group (2.08 ± 1.45 vs 2.73 ± 1.69, p = .039), and there was no significant difference at the other time points of VAS score in two groups. The inflammation markers, knee swelling, knee ROM and KSS score were not statistically different. Vomiting and other complications occurrence were not significantly different between the two groups. CONCLUSIONS: Intraoperative periarticular injection of glucocorticoids has similar analgesic effect compared to intravenous in the postoperative period following TKA and may be even more effective on the second postoperative day. In addition, periarticular injection of glucocorticoids does not impose an excess risk or complication on patients.

Shikonin and chitosan-silver nanoparticles synergize against triple-negative breast cancer through RIPK3-triggered necroptotic immunogenic cell death.

Necroptotic immunogenic cell death (ICD) can activate the human immune system to treat the metastasis and recurrence of triple-negative breast cancer (TNBC). However, developing the necroptotic inducer and precisely delivering it to the tumor site is the key issue. Herein, we reported that the combination of shikonin (SHK) and chitosan silver nanoparticles (Chi-Ag NPs) effectively induced ICD by triggering necroptosis in 4T1 cells. Moreover, to address the lack of selectivity of drugs for in vivo application, we developed an MUC1 aptamer-targeted nanocomplex (MUC1@Chi-Ag@CPB@SHK, abbreviated as MUC1@ACS) for co-delivering SHK and Chi-Ag NPs. The accumulation of MUC1@ACS NPs at the tumor site showed a 6.02-fold increase compared to the free drug. Subsequently, upon reaching the tumor site, the acid-responsive release of SHK and Chi-Ag NPs from MUC1@ACS NPs cooperatively induced necroptosis in tumor cells by upregulating the expression of RIPK3, p-RIPK3, and tetrameric MLKL, thereby effectively triggering ICD. The sequential maturation of dendritic cells (DCs) subsequently enhanced the infiltration of CD8+ and CD4+ T cells in tumors, while inhibiting regulatory T cells (Treg cells), resulting in the effective treatment of primary and distal tumor growth and the inhibition of TNBC metastasis. This work highlights the importance of nanoparticles in mediating drug interactions during necroptotic ICD.

Dietary ferulic acid improves growth performance of broilers via enhanced intestinal antioxidant capacity and barrier function.

Objective: In this study, the effects of dietary ferulic acid (FA) on the growth traits, antioxidant capacity, and intestinal barrier function of broilers were investigated. Methods: In total, 192 male Arbor Acres broilers were randomly allocated to one of three dietary groups (8 replicates of 8 birds each): control (CON) group (basal diet), FA100 group (basal diet + 100 mg/kg FA), or FA200 group (basal diet + 200 mg/kg FA). The duration of the feeding trial was 42 days. Results: higher average daily gain (ADG) and lower feed to gain (F/G) ratio during day 0 to day 21 were found in the FA100 and FA200 groups, while higher ADG and lower F/G during day 21 to day 42 were only found in FA200 group, compared to the CON group (p < 0.05). Serum levels of MDA and DAO on day 21 were lower in the FA100 and FA200 groups and those on day 42 were lower in the FA200 group, while GSH-Px level in the FA100 and FA200 groups on day 21 and that in the FA200 group on day 42 were increased (p < 0.05). On day 21, jejunal GSS expression was upregulated in the FA200 group (p < 0.05), while jejunal and ileal expression of NRF2 and Occludin as well as ileal expression of GPX1 and ZO1 were increased in the FA100 and FA200 groups compared to the CON group (p < 0.05). On day 42, mRNA expression of GSS, NRF2, SOD1, and GPX1 in the jejunum and ileum as well as Claudin2 in the jejunum and Occludin in the ileum were increased in the FA200 group (p < 0.05). Conclusion: Dietary FA addition could improve the growth performance, antioxidant capacity, and gut integrity of broilers. The current findings provided evidences that the adoption of FA can be as nutrition intervention measure to achieve high-efficient broiler production for poultry farmers.

Ruminal degradation characteristics of bagasse with different fermentation treatments in the rumen of beef cattle.

This experiment aimed to study the degradation characteristics of bagasse after three fermentation treatments in beef cattle. Bagasse 1 was treated with 0.3% lactic acid bacteria (w/w). Bagasse 2 was treated with 0.3% mixed strains (Saccharomyces cerevisiae, Aspergillus niger, Aspergillus oryzae, and lactic acid bacteria at 2:1:1:1). Bagasse 3 was treated with 0.1% cellulase and 0.1% xylanase in addition to 0.3% mixed strains of bagasse 2. The dry matter (DM), crude ash (ASH), crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) in the bagasses were determined. Compared to the control bagasse (without the strain and enzyme treatments), three fermented bagasses showed higher DM after 4 h fermentation. The CP and ASH contents in fermented bagasse 3 were the highest, while the contents of NDF and ADF in fermented bagasse 3 were the lowest among all the groups. The effective degradability of DM, CP, NDF, and ADF was highest in fermented bagasse 3 among the evaluated bagasse feed, followed by fermented bagasse 2 > fermented bagasse 1 > bagasse. Overall, fermented bagasse 3 was better than the control and other treated bagasses, thus fermented bagasse 3 is a hopeful source for ruminant diet of beef cattle.

Effects of replacing hybrid giant napier with sugarcane bagasse and fermented sugarcane bagasse on growth performance, nutrient digestibility, rumen fermentation characteristics, and rumen microorganisms of Simmental crossbred cattle.

This study investigated the effects of replacing hybrid giant napiers with sugarcane bagasse and fermented sugarcane bagasse on the growth performance, apparent nutrient digestibility, rumen fermentation characteristics, and rumen microorganisms of Simmental crossbred cattle. Twenty-one Simmental crossbred cattle with similar initial body weight (363.42 ± 8.67 kg) were randomly divided into three groups: Group CON (20% hybrid giant napier +45% distillers grains +35% concentrate mixture), Group SB (20% sugarcane bagasse +45% distillers grains +35% concentrate mixture), and Group FSB (20% fermented sugarcane bagasse +45% distillers grains +35% concentrate mixture). The average daily weight gain in the SB group was lower than in the CON group, no significant difference was found between the CON and FSB groups. The feed conversion ratio of the CON and FSB groups was lower compared to the SB group. The apparent digestibility of neutral detergent fiber and acid detergent fiber in the SB group was lower than in the CON group, no significant difference was found between the CON and FSB groups. The levels of NH3-N, microbial protein, acetate, propionate, butyrate, isobutyrate, and total volatile fatty acids were higher in the CON and FSB groups than in the SB group, no significant difference was found between the CON and FSB groups. The relative abundances of Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, Prevotellaceae_UCG-003, Saccharofermentans, and Eubacteriumcoprostanoligenes_group were lower in the CON and FSB groups compared to the SB group. The relative abundance of Succiniclasticum was highest in the FSB group, followed by the CON group and then the SB group. Correlation analysis showed that the relative abundance of Succiniclasticum was positively correlated with propionate and NH3-N content, while the relative abundance of Rikenellaceae_RC9_gut_group was inversely correlated with NH3-N content. Gene function prediction indicated that fermented sugarcane bagasse promoted rumen microbial amino acid metabolism. In conclusion, replacing hybrid giant napiers with 20% sugarcane bagasse negatively affected the growth performance of Simmental crossbred cattle, while the addition of 20% fermented sugarcane bagasse had no adverse effects on growth performance and rumen fermentation characteristics, and did not alter the abundance of the rumen core flora in Simmental crossbred cattle.

The spatiotemporal journey of nanomedicines in solid tumors on their therapeutic efficacy.

The rapid development of nanomedicines is revolutionizing the landscape of cancer treatment, while effectively delivering them into solid tumors remains a formidable challenge. Currently, there is a huge disconnect on therapeutic response between regulatory approved nanomedicines and laboratory reported nanoparticles. The discrepancy is mainly resulted from the failure of using the classic overall pharmacokinetics behaviors of nanomedicines in tumors to predict the antitumor efficacy. Increasing evidence has revealed that the therapeutic efficacy predominantly relies on the intratumoral spatiotemporal distribution of nanomedicines. This review focuses on the spatiotemporal distribution of systemically administered chemotherapeutic nanomedicines in solid tumor. Firstly, the intratumoral biological barriers that regulate the spatiotemporal distribution of nanomedicines are described in detail. Next, the influences on antitumor efficacy caused by the spatial distribution and temporal drug release of nanomedicines are emphatically analyzed. Then, current methodologies for evaluating the spatiotemporal distribution of nanomedicines are summarized. Finally, the advanced strategies to positively modulate the spatiotemporal distribution of nanomedicines for an optimal tumor therapy are comprehensively reviewed.

pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy.

Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.

Effects of Dried Blueberry Pomace and Pineapple Pomace on Growth Performance and Meat Quality of Broiler Chickens.

The purpose of this study was to investigate the effects of dried blueberry pomace (BP) and pineapple pomace (PP) on the growth performance and meat quality of broiler chickens. A total of 240 1-day-old Ross 308 broiler chickens were randomly divided into 3 groups, with 10 replicates per treatment group and 8 birds per replicate (4 males and 4 females). The three groups were the control (CON) group, the 3% BP group, and 3% PP group. The entire trial period lasted 42 days. The results show that the average daily feed intake, average daily gain, and feed-to-gain ratio of the BP group and the PP group were not significantly different from those in the CON group (p > 0.05). Adding BP to the diet significantly reduced the proportion of liver and giblets (p < 0.05). Adding PP to the diet significantly reduced the proportion of liver, while the proportion of gizzard significantly increased (p < 0.05). The pH24h and L* of breast muscles were significantly lower in the PP group than in the CON group (p < 0.05). The water-holding capacity of the leg muscles in the BP group and the PP group was significantly lower than that in the CON group (p < 0.05). The crude protein content of breast muscle and the ether extract content of leg muscle in the BP group were significantly lower than those in the CON group (p < 0.05). In conclusion, the addition of 3% BP and PP to broiler chickens' diets had no adverse effects on growth performance or meat quality.

The Expression Patterns of Exogenous Plant miRNAs in Chickens.

(1) Background: MicroRNAs (miRNAs) are involved in a variety of biological processes, such as cell proliferation, cell differentiation, and organ development. Recent studies have shown that plant miRNAs may enter the diet and play physiological and/or pathophysiological roles in human health and disease; however, little is known about plant miRNAs in chickens. (2) Methods: Here, we analyzed miRNA sequencing data, with the use of five Chinese native chicken breeds and six different tissues (heart, liver, spleen, lung, kidney, and leg muscle), and used Illumina sequencing to detect the expression of plant miRNAs in the pectoralis muscles at fourteen developmental stages of Tibetan chickens. (3) Results: The results showed that plant miRNAs are detectable in multiple tissues and organs in different chicken breeds. Surprisingly, we found that plant miRNAs, such as tae-miR2018, were detectable in free-range Tibetan chicken embryos at different stages. The results of gavage feeding experiments also showed that synthetic tae-miR2018 was detectable in caged Tibetan chickens after ingestion. The analysis of tae-miR2018 showed that its target genes were related to skeletal muscle organ development, regulation of mesodermal cell fate specification, growth factor activity, negative regulation of the cell cycle, and regulation of growth, indicating that exogenous miRNA may regulate the development of chicken embryos. Further cell cultures and exogenous miRNA uptake assay experiments showed that synthetic wheat miR2018 can be absorbed by chicken myoblasts. (4) Conclusions: Our study found that chickens can absorb and deposit plant miRNAs in various tissues and organs. The plant miRNAs detected in embryos may be involved in the development of chicken embryos.

Dietary Methionine Increased the Growth Performances and Immune Function of Partridge Shank Broilers after Challenged with Coccidia.

The present study investigated the effects of methionine (Met) on growth, immune function, and antioxidant capacity in partridge shank broilers, which were treated with either an anticoccidial drug or a coccidia vaccine. Chickens were fed five graded levels of Met (0.33%, 0.39%, 0.45%, 0.51%, or 0.57%) for 21 days in combination with the drug or vaccine. The results revealed that an optimal level of Met supplementation (1) increased ADFI (average daily feed intake), ADG (average daily gain), and F/G values (feed-to-gain ratio), indicating improved production; (2) increased OPG levels (oocysts per gram feces), intestinal lesion scores, bursa of Fabricius and thymus indexes, and sIgA content; (3) improved GSH-Px activities, and increased content levels of T-protein, albumin, and urea nitrogen. In addition, birds in the anticoccidial drug group had higher final weights, higher ADFI and ADG values, as well as lower F/G values, compared with birds in the vaccine group, indicating that coccidia vaccine reduces the performance of broilers. In conclusion, we found that an optimal level of dietary Met improved the production of partridge shank broilers, and this result might be related to immune function and antioxidant capacity. Optimal levels of digestible Met in terms of production performance (ADG and F/G) and immune function (sIgA in ileum mucosa) in partridge shank broilers (1-21 days) were found to be 0.418, 0.451, and 0.451 of diet, respectively, when birds were given anticoccidial drug treatment, with corresponding figures of 0.444, 0.455, and 0.452% when the coccidia vaccine was administered.

Rethinking nanoparticulate polymer-drug conjugates for cancer theranostics.

Polymer-drug conjugates (PDCs) fabricated as nanoparticles have hogged the limelight in cancer theranostics in the past decade. Many researchers have devoted to developing novel and efficient polymeric drug delivery system since the first generation of poly(N-[2-hydroxypropyl]methacrylamide) copolymer-drug conjugates. However, none of them has been approved for chemotherapy in clinic. An ideal PDC nanoparticle for cancer theranostics should possess several properties, including prolonged circulation in blood, sufficient accumulation and internalization in tumors, and efficient drug release in target sites. To achieve these goals, it is important to rationally design the nanoparticulate PDCs based on circulation, accumulation, penetration, internalization, and drug release (CAPIR) cascade. Specifically, CAPIR cascades are divided into five steps: (1) circulation in the vascular compartment without burst release, (2) accumulation in tumors via enhanced permeability and retention effect, (3) subsequent penetration into the deep regions of tumors, (4) internalization into tumor cells, and (5) release of drugs as free molecules to exert their pharmacological effects. In this review, we focus on the development and novel approaches of nanoparticulate PDCs based on CAPIR cascade, and provide an outlook on future clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Gut microbiota and meat quality.

Sustainable meat production is important to providing safe and quality protein sources for humans worldwide. Intensive artificial selection and high energy input into the diet of many commercial animals for the last decade has significantly increased the daily gain of body weight and shortened the raising period, but unexpectedly decreased the meat quality. The gastrointestinal tract of animals harbors a diverse and complex microbial community that plays a vital role in the digestion and absorption of nutrients, immune system development, pathogen exclusion, and meat quality. Fatty acid composition and oxidative stress in adipose and muscle tissue influences meat quality in livestock and poultry. Recent studies showed that nutraceuticals are receiving increased attention, which could alter the intestinal microbiota and regulate the fat deposition and immunity of hosts to improve their meat quality. Understanding the microbiota composition, the functions of key bacteria, and the host-microbiota interaction is crucial for the development of knowledge-based strategies to improve both animal meat quality and host health. This paper reviews the microorganisms that affect the meat quality of livestock and poultry. A greater understanding of microbial changes that accompany beneficial dietary changes will lead to novel strategies to improve livestock and poultry meat product quality.

Key miRNAs and Genes in the High-Altitude Adaptation of Tibetan Chickens.

Tibetan chickens living at high altitudes show specific physiological adaptations to the extreme environmental conditions. However, the regulated base of how chickens adapt to high-altitude habitats remains largely unknown. In this study, we sequenced 96 transcriptomes (including 48 miRNA and 48 mRNA transcriptomes of heart, liver, lung, and brain) and resequenced 12 whole genomes of Tibetan chickens and Peng'xian yellow chickens. We found that several miRNAs show the locally optimal plastic changes that occurred in miRNAs of chickens, such as miR-10c-5p, miR-144-3p, miR-3536, and miR-499-5p. These miRNAs could have effects on early adaption to the high-altitude environment of chickens. In addition, the genes under selection between Tibetan chickens and Peng'xian yellow chickens were mainly related to oxygen transport and oxidative stress. The I-kappa B kinase/NF-kappa B signaling pathway is widely found for high-altitude adaptation in Tibetan chickens. The candidate differentially expressed miRNAs and selected genes identified in this study may be useful in current breeding efforts to develop improved breeds for the highlands.

A pyroptosis nanotuner for cancer therapy.

Pyroptosis is a gasdermin-mediated programmed necrosis that occurs via membrane perforation and that can be exploited for biomedical applications in cancer therapy. However, inducing specific pyroptotic cancer cell death while sparing normal cells is challenging. Here, we report an acid-activatable nanophotosensitizer library that can be used to spatiotemporally target distinct stages of endosomal maturation, enabling tunable cellular pyroptosis. Specific activation of phospholipase C signalling transduction in early endosomes triggers gasdermin-E-mediated pyroptosis, which is dramatically reduced when acid-activatable nanophotosensitizers are transported into late endosomes/lysosomes. This nanotuner platform induces pyroptotic cell death with up to 40-fold tunability in various gasdermin-E-positive human cancers, resulting in enhanced anti-tumour efficacy and minimized systemic side effects. This study offers new insights into how to engineer nanomedicines with tunable pyroptosis activity through specific targeting of distinct endocytic signalling for biomedical applications.

Dissecting extracellular and intracellular distribution of nanoparticles and their contribution to therapeutic response by monochromatic ratiometric imaging.

Efficient delivery of payload to intracellular targets has been identified as the central principle for nanomedicine development, while the extracellular targets are equally important for cancer treatment. Notably, the contribution of extracellularly distributed nanoparticles to therapeutic outcome is far from being understood. Herein, we develop a pH/light dual-responsive monochromatic ratiometric imaging nanoparticle (MRIN), which functions through sequentially lighting up the intracellular and extracellular fluorescence signals by acidic endocytic pH and near-infrared light. Enabled by MRIN nanotechnology, we accurately quantify the extracellular and intracellular distribution of nanoparticles in several tumor models, which account for 65-80% and 20-35% of total tumor exposure, respectively. Given that the majority of nanoparticles are trapped in extracellular regions, we successfully dissect the contribution of extracellularly distributed nanophotosensitizer to therapeutic efficacy, thereby maximize the treatment outcome. Our study provides key strategies to precisely quantify nanocarrier microdistribtion and engineer multifunctional nanomedicines for efficient theranostics.