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Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading to low absorption and bioavailability, and safety concerns owing to tight junction openings. Here we report a zwitterionic micelle platform featuring a virus-mimetic zwitterionic surface, a betaine side chain and an ultralow critical micelle concentration, enabling drug penetration through the mucus and efficient transporter-mediated epithelial absorption without the need for tight junction opening. This micelle platform was used to fabricate a prototype oral insulin formulation by encapsulating a freeze-dried powder of zwitterionic micelle insulin into an enteric-coated capsule. The biocompatible oral insulin formulation shows a high oral bioavailability of >40%, offers the possibility to fine tune insulin acting profiles and provides long-term safety, enabling the oral delivery of protein drugs.A zwitterionic micelle platform enables the oral delivery and high bioavailability of insulin by transporting the protein across mucus and epithelial barriers in the gut without opening tight junctions.

Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53 -null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment. The p53 tumor suppressor gene is frequently mutated in liver cancer. Here the authors show that restoration of p53 expression with a mRNA nanoparticle platform elicits anti-tumor immune responses and promotes response to immune checkpoint blockade in preclinical models of p53-null hepatocellular carcinoma.

Postoperative adhesions are most common issues for almost any types of abdominal and pelvic surgery, leading to adverse consequences. Pharmacological treatments and physical barrier devices are two main approaches to address postoperative adhesions but can only alleviate or reduce adhesions to some extent. There is an urgent need for a reliable approach to completely prevent postoperative adhesions and to significantly improve the clinical outcomes, which, however, is unmet with current technologies. Here we report that by applying a viscous, cream-like yet injectable zwitterionic polymer solution to the traumatized surface, postoperative adhesion was completely and reliably prevented in three clinically relevant but increasingly challenging models in rats. The success rate of full prevention is over 93% among 42 animals tested, which is a major leap in antiadhesion performance. Clinically used Interceed film can hardly prevent the adhesion in any of these models. Unlike current antiadhesion materials serving solely as physical barriers, the “nonfouling” zwitterionic polymer functioned as a protective layer for antiadhesion applications with the inherent benefit of resisting protein/cell adhesions. The nonfouling nature of the polymer prevented the absorption of fibronectins and fibroblasts, which contribute to the initial and late-stage development of the adhesion, respectively. This is the key working mechanism that differentiated our “complete prevention” approach from current underperforming antiadhesion materials. This work implies a safe, effective, and convenient way to fully prevent postoperative adhesions suffered by current surgical patients.

Tillage practices can change the soil environment (including soil properties and enzyme activity) and the rhizosphere microbial community, thereby inducing changes in root growth and the nutrient uptake capacity. This study was carried out on a long-term (since 1983) tillage field experimental platform. It aimed to explore the effects of tillage practices and growth stages on maize root development, soil properties, and the rhizosphere microbial community. The results can provide a theoretical basis for the further analysis of crop–soil–microbial interactions. In our study, we investigated the abundance and diversity of the rhizosphere microbial community and their relationship with root growth characteristics and soil factors under long-term (since 1983) conventional tillage (CT), subsoil tillage (ST), and no-tillage (NT) practices using quantitative PCR and high-throughput 16S/ITS sequencing. In 2020, at the 30-days-after-silking (VT 30) stage, NT increased the root length, root dry weight, N accumulation, and N uptake rate of maize roots compared with CT by 16.7%, 16.3%, 41.9%, and 41.9%, respectively. In 2020, at the 12th leaf (V12) and VT 30 stages of maize, NT significantly increased the contents of soil total nitrogen (by 16.3% and 11.0%, respectively), total carbon (by 23.9% and 12.9%, respectively), soil organic matter (by 24.8% and 10.3%, respectively), and soil urease activity (by 5.5% and 5.6%, respectively) compared with CT. Moreover, NT significantly increased the bacterial and fungal abundances compared with CT. Redundancy analysis (RDA) showed that the variation in the microbial structure correlated markedly with the alteration in root indicators, soil properties, and enzyme activities. Long-term no-tillage improved the abundance and diversity of rhizosphere microbial communities by increasing the soil total nitrogen, total carbon, and soil organic matter, and promoted the N accumulation of roots and their uptake rate.

Continuous subcutaneous insulin infusion (CSII) is an essential insulin replacement therapy in the management of diabetes. However, the longevity of clinical CSII is limited by skin complications, by impaired insulin absorption and by occlusions associated with the subcutaneous insertion of CSII catheters, which require replacement and rotation of the insertion site every few days. Here we show that a biodegradable zwitterionic gel covering the tip end of commercial off-the-shelf CSII catheters fully resolves early skin irritations, extends the longevity of catheters and improves the rate of insulin absorption (also with respect to conventional syringe-based subcutaneous injection) for longer than 6 months in diabetic mice, and by 11 days in diabetic minipigs (from 2 to 13 days, under standard CSII-wearing conditions of insulin pump therapy and in a continuous basal-plus-bolus-infusion setting). The implanted gel displayed anti-inflammatory and anti-foreign-body-reaction properties and promoted the local formation of new blood vessels. The gel is subcutaneously injected before the tip of catheter is inserted into it, and should be generally applicable to CSII catheters and other implantable devices. A biodegradable zwitterionic gel covering the tip end of commercial catheters for the continuous and subcutaneous infusion of insulin extends the longevity of the catheters and improves the rate of insulin absorption in diabetic mice and minipigs.

Cultivar and sowing date selection are major factors in determining the yield potential of any crop and in any region. To explore how climate change affects these choices, this study performed a regional scale analysis using the well-validated APSIM-maize model for the Northeast China Plain (NEC) which is the leading maize (Zea mays L.) producing area in China. Results indicated that high temperature had a significantly negative effect on grain yield, while effective accumulated temperature and solar radiation had significant positive effects on grain yield and kernel number. Cloudy and rainy weather in flowering stage had significant negative effects on kernel number. Delayed sowing led to less cloudy and rainy weather during flowering and reduced the negative effect on kernel number. Higher diurnal thermal range and less precipitation during the grain-filling stage also increased the 1000-kernel weight. Delayed sowing, however, also significantly increased the risk of early senescence and frost (>80%) in middle and high latitude areas. In the middle and high latitude areas of the NEC, the grain yield of a long-season cultivar (LS) under early sowing (I) (6.2–19.9%) was significantly higher than under medium sowing (II) or late sowing (III), and higher than that of an early sown (I) short-season (SS) and medium-season cultivar (MS). In the low latitude area of the NEC, the grain yield of MS under medium sowing date (II) was higher than that under I and III, meanwhile, this was also higher than that of SS and LS. Therefore, under climate warming, LS sown earlier in high and medium latitudes and MS sown medium in low latitude were the appropriate cultivar and sowing date choices, which could mitigate the stress of high temperatures and reduce the risk of early senescence and frost. Cultivar and sowing date selection are effective measures to alleviate negative effects of climate change on maize production in the NEC, and provides valuable advice for breeders on cultivar selection, and the choice of varieties and sowing dates for farmers in actual production.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, particularly due to the limited effectiveness of current therapeutic options for advanced-stage disease. The efficacy of traditional treatments is often compromised by the intricate liver microenvironment and the inherent heterogeneity. RNA-based therapeutics offer a promising alternative, utilizing the innovative approach of targeting aberrant molecular pathways and modulating the tumor microenvironment. The integration of nanotechnology in this field, through the development of advanced nanocarrier delivery systems, especially lipid nanoparticles (LNPs), polymer nanoparticles (PNPs), and bioinspired vectors, enhances the precision and efficacy of RNA therapies. This review highlights the significant progress in RNA nanotherapeutics for HCC treatment, covering micro RNA (miRNA), small interfering RNA (siRNA), message RNA (mRNA), and small activating RNA (saRNA) mediated gene silencing, therapeutic protein restoration, gene activation, cancer vaccines, and concurrent therapy. It further comprehensively discusses the prevailing challenges within this therapeutic landscape and provides a forward-looking perspective on the potential of RNA nanotherapeutics to transform HCC treatment.

Tillage is an important management tool for tackling and promoting water conservation and improving crop yield. As one of the important nutrients in plant growth, K is involved in important processes such as osmoregulation, photosynthesis and metabolite transport, and plays a particularly critical role in improving crop yield and quality. In the long-term positioning platform of the tillage method, a 2-yr field experiment was conducted in 2019-2020 in maize (Zea mays L.) Three tillage methods: conventional tillage (CT), subsoil tillage (ST), and no-tillage (NT) and two planting densities 6x[10.sup.4] (D1) and 9xl0 (4) plants [ha.sup.-1] (D2) were set up in the experiment. The results showed that yield and K translocation efficiency (KTE) were significantly higher in NT than in CT at Dl (by 4.7% and 12.2%) and D2 (by 14.0% and 13.9%), respectively. At maturity stage in 2019, population DM accumulation after silking (DMA) was significantly higher in NT (by 11.0% and 16.9%) than in CT at Dl and D2. Correlation analysis revealed that yield was significantly positive correlated with ears (r = 0.57***) and DMA (r = 0.64***). Potassium translocation and K harvest index were positively correlated with KTE. Under spring drought year, the long-term no-tillage had a significant yield increase, mainly through the increase in 1000-kernel weight. The increase in K efficiency was mainly through the influence of DM accumulation and distribution, and K accumulation in grain.

Tillage is an important management tool for tackling and promoting water conservation and improving crop yield. As one of the important nutrients in plant growth, K is involved in important processes such as osmoregulation, photosynthesis and metabolite transport, and plays a particularly critical role in improving crop yield and quality. In the long-term positioning platform of the tillage method, a 2-yr feld experiment was conducted in 2019-2020 in maize (Zea mays L.) Three tillage methods: conventional tillage (CT), subsoil tillage (ST), and no-tillage (NT) and two planting densities 6×104 (D1) and 9×104 plants ha-1 (D2) were set up in the experiment. The results showed that yield and K translocation effciency (KTE) were signifcantly higher in NT than in CT at D1 (by 4.7% and 12.2%) and D2 (by 14.0% and 13.9%), respectively. At maturity stage in 2019, population DM accumulation after silking (DMA) was signifcantly higher in NT (by 11.0% and 16.9%) than in CT at D1 and D2. Correlation analysis revealed that yield was signifcantly positive correlated with ears (r = 0.57***) and DMA (r = 0.64***). Potassium translocation and K harvest index were positively correlated with KTE. Under spring drought year, the long-term no-tillage had a signifcant yield increase, mainly through the increase in 1000-kernel weight. The increase in K effciency was mainly through the infuence of DM accumulation and distribution, and K accumulation in grain.

Sensory neurons within the dorsal root ganglion (DRG) are the primary trigger of pain, relaying activity about noxious stimuli from the periphery to the central nervous system; however, targeting DRG neurons for pain management has remained a clinical challenge. Here, we demonstrate the use of lipid nanoparticles (LNPs) for effective intrathecal delivery of small interfering RNA (siRNA) to DRG neurons, achieving potent silencing of the transient receptor potential vanilloid 1 (TRPV1) ion channel that is predominantly expressed in nociceptor sensory neurons. This leads to a reversible interruption of heat-, capsaicin-, and inflammation-induced nociceptive conduction, as observed by behavioral outputs. Our work provides a proof-of-concept for intrathecal siRNA therapy as a novel and selective analgesic modality.