ROS-responsive core-shell nano-inhibitor impedes pyruvate metabolism for reinforced photodynamic therapy and interrupted pre-metastatic niche formation.

The formation of pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor requires the communication between the tumor cells and the host environment. Pyruvate is a fundamental nutrient by which the tumor cells metabolically reshape the extracellular matrix in the lung to facilitate their own metastatic development. Here we report a combination regimen by integrating the photo-sensitizer and the mitochondrial pyruvate carrier (MPC) inhibitor in a dendritic polycarbonate core-hyaluronic acid shell nano-platform with multivalent reversible crosslinker embedded in it (DOH-NI+L) to reinforce photodynamic therapy (PDT) toward the primary tumor and interrupt PMN formation in the lung via impeding pyruvate uptake. We show that DOH-NI+L mediates tumor-specific MPC inhibitor liberation, inhibiting the aerobic respiration for facilitated PDT and restraining ATP generation for paralyzing cell invasion. Remarkably, DOH-NI+L is demonstrated to block the metabolic crosstalk of tumor cell-host environment by dampening pyruvate metabolism, provoking a series of metabolic responses and resulting in the pulmonary PMN interruption. Consequently, DOH-NI+L realizes a significant primary tumor inhibition and an efficient pulmonary metastasis prevention. Our research extends nano-based anti-metastatic strategies aiming at PMN intervention and such a dendritic core-shell nano-inhibitor provides an innovative paradigm to inhibit tumor growth and prevent metastasis efficiently. STATEMENT OF SIGNIFICANCE: In the progression of cancer metastasis, the formation of a pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor is one of the rate-limiting stages. The current nano-based anti-metastatic modalities mainly focus on targeted killing of tumor cells and specific inhibition of tumor cell invasion, while nanomedicine-mediated interruption of PMN formation has been rarely reported. Here we report a combination regimen by integrating a photo-sensitizer and an inhibitor of mitochondrial pyruvate carrier in a dendritic core-shell nano-platform with a reversible crosslinker embedded in it to reinforce PDT toward the primary tumor and interrupt PMN formation via impeding the uptake of pyruvate that is a fundamental nutrient facilitating aerobic respiration and PMN formation. Our research proposed a nano-based anti-metastatic strategy aiming at PMN intervention.

Photothermal-controlled NO-releasing Nanogels reverse epithelial-mesenchymal transition and restore immune surveillance against cancer metastasis.

Metastasis leads to high mortality among cancer patients. It is a complex, multi-step biological process that involves the dissemination of cancer cells from the primary tumor and their systemic spread throughout the body, primarily through the epithelial-mesenchymal transition (EMT) program and immune evasion mechanisms. It presents a challenge in how to comprehensively treat metastatic cancer cells throughout the entire stage of the metastatic cascade using a simple system. Here, we fabricate a nanogel (HNO-NG) by covalently crosslinking a macromolecular nitric oxide (NO) donor with a photothermal IR780 iodide-containing hyaluronic acid derivative via a click reaction. This enables stable storage and tumor-targeted, photothermia-triggered release of NO to combat tumor metastasis throughout all stages. Upon laser irradiation (HNO-NG+L), the surge in NO production within tumor cells impairs the NF-κB/Snail/RKIP signaling loop that promotes the EMT program through S-nitrosylation, thus inhibiting cell dissemination from the primary tumor. On the other hand, it induces immunogenic cell death (ICD) and thereby augments anti-tumor immunity, which is crucial for killing both the primary tumor and systemically distributed tumor cells. Therefore, HNO-NG+L, by fully leveraging EMT reversal, ICD induction, and the lethal effect of NO, achieved impressive eradication of the primary tumor and significant prevention of lung metastasis in a mouse model of orthotropic 4T1 breast tumor that spontaneously metastasizes to the lungs, extending the NO-based therapeutic approach against tumor metastasis.

Dually crosslinked degradable polyionic micelles for sustained glucose-responsive insulin release.

Glucose -sensitive delivery systems hold great promise as a therapeutic approach for high-incidence diabetes owing to their ability to release insulin whenever elevated glycemia is detected. However, they are unstable in a hyperglycemic environment, which leads to short-term sustained insulin release. Herein, we designed dually crosslinked insulin polyionic micelles (DCM@insulin) based on triblock polymers of o-glycol and phenylboronic acid-functionalized poly(ethylene glycol)-poly(dimethylamino carbonate)-poly(dimethylamino-trimethylene carbonate) (mPEG-P(AC-co-MPD)-PDMAC and mPEG-P(AC-co-MAPBA)-PDMATC, respectively) for sustained glucose-responsive insulin release. DCM@insulin with a phenylboronic acid ester structure (first crosslinking structure) enhanced glycemic responsiveness by regulating insulin release in a hyperglycemic environment. Additionally, the UV-crosslinking structure (second crosslinking structure) formed by the residual double bonds in AC units endowed DCM@insulin with the ability to effectively protect the loaded insulin against protease degradation and avoid burst release under multiple insulin release. The in vivo findings demonstrated that DCM@insulin effectively maintained glycemic levels (BGLs) within the normal range for 6 h in comparison to single-crosslinked micelles (SCM@insulin). Therefore, the glucose-responsive and dually crosslinked polyionic micelle system exhibits potential as a viable option for the treatment of diabetes.

Design and performance analysis of a new inferior vena cava filter.

This study proposes a novel inferior vena cava filter (IVCF) design, "Lotus," aiming to enhance release stability and endothelialization. A catheter-filter-vessel model was established for IVCF property analysis, validated by comparing numerical simulations and in vitro tests. Lotus's mechanical properties were analyzed, and optimization suggestions are provided. Compared to existing clinical filters, Lotus demonstrates improved release stability and thrombus capture ability. This work suggests Lotus as a potential technical reference for improved IVCF treatment.

Recent developments in the fabrication of food microparticles and nanoparticles using microfluidic systems.

Microfluidics is revolutionizing the production of microparticles and nanoparticles, offering precise control over dimensions and internal structure. This technology facilitates the creation of colloidal delivery systems capable of encapsulating and releasing nutraceuticals. Nutraceuticals, often derived from food-grade ingredients, can be used for developing functional foods. This review focuses on the principles and applications of microfluidic systems in crafting colloidal delivery systems for nutraceuticals. It explores the foundational principles behind the development of microfluidic devices for nutraceutical encapsulation and delivery. Additionally, it examines the prospects and challenges with using microfluidics for functional food development. Microfluidic systems can be employed to form emulsions, liposomes, microgels and microspheres, by manipulating minute volumes of fluids flowing within microchannels. This versatility can enhance the dispersibility, stability, and bioavailability of nutraceuticals. However, challenges as scaling up production, fabrication complexity, and microchannel clogging hinder the widespread application of microfluidic technologies. In conclusion, this review highlights the potential role of microfluidics in design and fabrication of nutraceutical delivery systems. At present, this technology is most suitable for exploring the role of specific delivery system features (such as particle size, composition and morphology) on the stability and bioavailability of nutraceuticals, rather than for large-scale production of nutraceutical delivery systems.

Ursodeoxycholic Acid-Decorated Zwitterionic Nanoparticles for Orally Liver-Targeted Close-Looped Insulin Delivery.

Oral insulin therapies targeting the liver and further simulating close-looped secretion face significant challenges due to multiple trans-epithelial barriers. Herein, ursodeoxycholic acid (UDCA)-decorated zwitterionic nanoparticles (NPs) (UC-CMs@ins) are designed to overcome these barriers, target the liver, and respond to glycemia, thereby achieving oral one-time-per-day therapy. UC-CMs@ins show excellent mucus permeability through the introduction of zwitterion (carboxy betaine, CB). Furthermore, UC-CMs@ins possess superior cellular internalization via proton-assisted amino acid transporter 1 (PAT1, CB-receptor) and apical sodium-dependent bile acid transporter (ASBT, UDCA-receptor) pathways. Moreover, UC-CMs@ins exhibit excellent endolysosomal escape ability and improve the basolateral release of insulin into the bloodstream via the ileal bile acid-binding protein and the heteromeric organic solute transporter (OSTα- OSTß) routes compared with non-UDCA-decorated C-CMs@ins. Therefore, CB and UDCA jointly overcome mucus and intestinal barriers. Additionally, UC-CMs@ins prevent insulin degradation in the gastrointestinal tract for crosslinked structure, improve insulin accumulation in the liver for UDCA introduction, and effectively regulate glycemia for "closed-loop" glucose control. Surprisingly, oral ingestion of UC-CMs@ins shows a superior effect on glycemia (≈22 h, normoglycemia) and improves postprandial glycemic levels in diabetic mice, illustrating the enormous potential of the prepared NPs as a platform for oral insulin administration in diabetes treatment.

PVA-based bulk microneedles capable of high insulin loading and pH-triggered degradation for multi-responsive and sustained hypoglycemic therapy.

"Closed-loop" insulin-loaded microneedle patche shows great promise for improving therapeutic outcomes and life quality for diabetes patients. However, it is typically hampered by limited insulin loading capacity, random degradation, and intricate preparation procedures for the independence of the "closed-loop" bulk microneedles. In this study, we combined the solubility of microneedles and "closed-loop" systems and designed poly(vinyl alcohol)-based bulk microneedles (MNs@GI) through in situ photopolymerization for multi-responsive and sustained hypoglycemic therapy, which significantly simplified the preparation process and improved insulin loading. GOx/insulin co-encapsulated MNs@GI with a phenylboronic ester structure improved glycemic responsiveness to control the insulin release under high glucose conditions and reduced inflammation risk in the normal skin. MNs@GI could further degrade to increase insulin release due to the crosslinked acetal-linkage hydrolysis in the presence of gluconic acid, which was caused by GOx-mediated glucose-oxidation in a hyperglycemic environment. The in vivo results showed that MNs@GI effectively regulated glycemic levels within the normal range for approximately 10 h compared to that of only insulin-loaded microneedles (MNs@INS). Consequently, the highly insulin-loaded, multi-responsive, and pH-triggered MN system has tremendous potential for diabetes treatment.

Super-small zwitterionic micelles enable the improvement of blood-brain barrier crossing for efficient orthotopic glioblastoma combinational therapy.

Glioblastoma multiforme (GBM) remains incurable in clinical, nanotechnology-based drug delivery strategies show promising perspective in alleviating GBM, while limited blood-brain-barrier (BBB) permeation, short blood half-live accompanied by the poor tumor accumulation and penetration, significantly restrict the therapeutic outcomes. Herein, a versatile super-small zwitterionic nano-system (MCB(S)) based on carboxybetaine (CB) zwitterion functionalized hyperbranched polycarbonate (HPCB) is developed to overcome the brain delivery challenges. After grafting with amino-functionalized IR780 (free IR780), the ultimate paclitaxel (PTX)-encapsulated micelles (MCB(S)-IR@PTX) are precisely activated by near-infrared (NIR) for accelerated drug release and effective combinational GBM therapy. Importantly, MCB(S)-IR@PTX with the crosslinked structure and CB zwitterion prolongs blood-circulation, and CB-zwitterion further facilitates BBB-traversing through betaine/γ-aminobutyric acid (GABA) transporter-1 (BGT-1) pathway. Combined with the benefit of super small-size, MCB(S)-IR@PTX highly accumulates at tumor sites and penetrates deeply, thus efficiently inhibiting tumor growth and strikingly improving survival time in U87MG orthotopic GBM-bearing mouse model. The ingenious nanoplatform furnishes a versatile strategy for delivering therapeutics into the brain and realizing efficient brain cancer therapy.

Prediction of enhanced drug solubility related to clathrate compositions and operating conditions: Machine learning study.

Although complexation technique has been documented as a promising strategy to enhance the dissolution rate and bioavailability of water-insoluble drugs, prediction of the enhanced drug solubility related to clathrate compositions and operating conditions is still a challenge. Herein, clathrate compositions (drug content (DC), drug molecular weight (M) and molar ratio (Ratio)), operating conditions (drug concentration (C), pH, pressure (P), temperature (T) and dissolution time (t)) under the different excipients (PEG, PVP, HPMC and cyclodextrin) as main solubilizers of the clathrates condition as input parameters were used to predict two indexes (drug dissolved percentage and dissolution efficiency) simultaneously through machine learning methodfor the first time. The results show that PVP as the main solubilizer of clathrates had higher prediction accuracy to the drug dissolved percentage, and HPMC as the main solubilizer of clathrates had higher prediction accuracy to the drug dissolution efficiency. In addition, the influence of various factors and interactions on the target variables were analyzed. This study affords achievable hints to the quantitative prediction of the drug solubility affected by various compositions and different operating conditions.

Two-in-One Polymeric NO-Donor Prodrugs Mediate Precision and Synergistic Prostate Cancer Treatment.

Chemotherapy predominates in clinical treatment of prostate cancer (PCa), while irreversible resistance to chemotherapeutics and severe side effects hinder the therapeutic efficacy, especially in castration-resistant PCa (CRPC). Herein, a bombesin (BBN)-decorated two-in-one prodrug (T-NO/E2-PMs) incorporating a polymeric nitric oxide (NO) donor and acetal-linked 17ß-estradiol (E2) in one backbone is developed, aiming to inhibit androgen receptor (AR) expression, reprogram the tumor microenvironment of CRPC, and enhance estradiol-mediated hypoxic CRPC therapy. Following efficient internalization mediated by BBN, T-NO/E2-PMs releases estradiol and NO in response to the unique intracellular environments. Both in vitro and in vivo studies demonstrate that the T-NO/E2-PMs nano-prodrug along with NO release potently downregulates AR levels to reverse CRPC and further enhances the chemo-sensitization of estradiol to PCa PC-3 cell apoptosis and the inhibition of metastasis. Collectively, this two-in-one nano-prodrug strategy offers a promising platform for construction of advanced nanomedicine to boost the therapeutic efficacy.

A glucose-responsive nitric oxide release hydrogel for infected diabetic wounds treatment.

Bacteria-infected chronic wound is one of the most serious complications of diabetes and characterized with high morbidity and risk of lower extremity amputation. Nitric oxide (NO) represents a promising strategy to accelerate wound healing through down-regulating inflammation, promoting angiogenesis and bacterial eradication. However, stimuli-responsive and control release of NO at the wound microenvironment remains a challenge. In this work, an injectable, self-healing and antibacterial hydrogel characterized with glucose-responsive and constant NO release behaviors has been engineered for diabetic wound management. The hydrogel (CAHG) is prepared by in situ crosslinking of L-arginine (L-Arg)-coupled chitosan and glucose oxidase (GOx)-modified hyaluronic acid based on Schiff-base reaction. The system is capable of mediating a continuous release of hydrogen peroxide (H2O2) and NO by the cascaded consumption of glucose and L-Arg in the presence of hyperglycemia environment. In vitro studies demonstrate that bacteria proliferation is significantly inhibited by CAHG hydrogel involving in the cascaded release of H2O2 and NO. More importantly, a full-thickness skin wound model on a diabetic mouse demonstrates that H2O2 and NO release from CAHG hydrogel exhibits a superior efficiency for wound healing through bacterial inhibition, down-regulation of pro-inflammatory factors and the elevation of M2-type macrophage, contributing to the collagen deposition and angiogenesis. In conclusion, CAHG hydrogel with excellent biocompatibility and glucose-responsive NO release characteristic can serve as a highly efficient therapeutic strategy for diabetic wound treatment.

[Effect of early fluid balance on the prognosis in severe acute pancreatitis].

OBJECTIVE: To observe the correlation between early fluid resuscitation and prognosis in patients with severe acute pancreatitis (SAP). METHODS: SAP patients admitted to the department of critical care medicine of the People's Hospital of Chuxiong Yi Autonomous Prefecture of Yunnan Province from June 2018 to December 2020 were enrolled and analyzed retrospectively. All patients were given the routine treatment according to their condition and relevant diagnostic According to their different prognosis, enrolled patients were divided into death group and survival group. The differences in gender, age, acute physiology and chronic health evaluation II (APACHE II) and Ranson score on admission between the two groups were analyzed. Taking 24 hours as an observation day, the fluid inflow, outflow, and net balance at the first, second, and third 24 hours after admission were recorded, and the ratio of the fluid inflow at the first 24 hours to the total fluid inflow in 72 hours (FV24 h-1 st) was calculated as a study index. Using 33% as the standard, compare the proportion of patients in the two groups who achieved FV24 h-1 st < 33%. The differences of various indicators between the two groups were compared, and the effect of early fluid balance on the prognosis of SAP patients was analyzed. RESULTS: Eighty-nine patients were included in the study (41 in the death group, 48 in the survival group). There were no statistically significant differences on age (years old: 57.6±15.2 vs. 49.5±15.2), gender (male: 61.0% vs. 54.2%), APACHE II score (18.0±2.4 vs. 17.3±2.3), and Ranson score (6.3±1.4 vs. 5.9±1.2) between the death group and the survival group at the time of admission on the intensive care unit (ICU) (all P > 0.05). The fluid intake of the death group in the first 24 hours, the second 24 hours and the third 24 hours after admission to ICU was significantly higher than that of the survival group, and the difference was statistically significant (mL: 4 138±832 vs. 3 535±1 058, 3 883±729 vs. 3 324±516, 3 786±490 vs. 3 212±609, all P < 0.05), and the fluid inflow in the death group at the first 24 hours was greater than 4 100 mL. After treatment, the fluid outflow of the death group at the three 24-hour periods after admission on the ICU was an increasing trend, but it was still significantly less than that of the survival group at the three 24-hour periods (mL: 1 242±465 vs. 1 795±819, 1 536±579 vs. 2 080±524, 1 610±585 vs. 2 932±752, all P < 0.01). Due to the fact that the total fluid inflow and total fluid outflow in the three 24-hour periods in the death group were more than those in the survival group, the net fluid balances in the three 24-hour periods in the death group were still significantly more than those in the survival group finally (mL: 2 896±782 vs. 1 740±725, 2 347±459 vs. 1 243±795, 2 176±807 vs. 338±289, all P < 0.01). There was no difference in FV24 h-1 st between the death group and survival group [FV24 h-1 st > 33%: 56.1% (23/41) vs. 54.2% (26/48), P > 0.05]. CONCLUSIONS: Fluid resuscitation is an important method for early treatment of SAP, but it also has many adverse reactions. Fluid resuscitation indexes such as fluid inflow, outflow, net balance, and FV24 h-1 st within 24 to 72 hours after admission are related to the prognosis of patients with SAP, and can be used as indicators to evaluate the prognosis of SAP. The optimized fluid resuscitation strategy can improve the prognosis of patients with SAP.

Reversibly "double locked" hydroxycamptothecin prodrug nanoparticles for targeted chemotherapy of lung cancer.

Prodrug assembled nanoparticles integrate the merits of both prodrug and nanoparticle, which significantly improve pharmacokinetic parameters, enhance tumorous accumulation and decrease adverse effects, while they are challenged by disassembly upon dilution in blood, masking the superiority of nanoparticles (NPs). Herein, a reversibly "double locked" hydroxycamptothecin (HCPT) prodrug nanoparticle decorated with cyclic RGD peptide (cRGD) is developed for safe and efficient chemotherapy of orthotopic lung cancer in mice. HCPT prodrug is constructed from acetal (ace)-linked cRGD-PEG-ace-HCPT-ace-acrylate polymer, which is self-assembled into the nanoparticles with "the first lock" of HCPT. Then the nanoparticles undergo the in situ UV-crosslinking of the acrylate residues for constructing "the second lock" of HCPT. The obtained "double locked" nanoparticles (T-DLHN) with simple and well-defined construction are demonstrated to possess extremely high stability against 100-fold dilution and acid-triggered "unlock" including de-crosslinking and liberation of the pristine HCPT. In an orthotopic lung tumor of mouse model, T-DLHN reveals a prolonged circulation time of about 5.0 h, superb lung tumor-homing capacity with tumorous drug uptake of about 7.15%ID/g, resulting in significantly boosted anti-tumor activity and reduced adverse effects. Hence, these nanoparticles utilizing "double lock" and acid-triggered "unlock" strategies represent a unique and promising nanoplatform for safe and efficient drug delivery. STATEMENT OF SIGNIFICANCE: Prodrug assembled nanoparticles have the unique properties of the well-defined structure, systemic stability, improved pharmacokinetics, passive targeting and decreased adverse effects. However, prodrug assembled NPs would disassemble against extensive dilution in the blood circulation when intravenously injected into the body. Herein, we have designed a cRGD-directed reversibly "double-locked" HCPT prodrug nanoparticle (T-DLHN) for safe and efficient chemotherapy of orthotopic A549 human lung tumor xenografts. Upon intravenous injection, T-DLHN can overcome the shortcoming of disassembly against extensive dilution, prolong the circulation time due to the "double locked" configuration and then mediate targeted drug delivery into the tumors. After uptaken into the cells, T-DLHN undergoes concurrent de-crosslinking and liberation of HCPT under acidic condition for enhanced chemotherapeutic efficacy with negligible adverse effects.

Crosslinked zwitterionic microcapsules to overcome gastrointestinal barriers for oral insulin delivery.

Oral insulin delivery has been extensively considered to achieve great patient compliance and convenience as well as favourable glucose homeostasis. However, its application is highly limited by the low insulin bioavailability owing to gastrointestinal barriers. Herein, we developed crosslinked zwitterionic microcapsules (CB-MCs@INS) based on a carboxyl betaine (CB)-modified poly(acryloyl carbonate-co-caprolactone) copolymer via the combination of microfluidics and UV-crosslinking to improve oral insulin delivery. CB-MC@INS microcapsules with high drug loading capacity (>40%) protected insulin from acid degradation in the harsh gastric environment. Through the introduction of CB-moieties, CB-MCs@INS possessed superior affinity for epithelial cells and improved insulin transport as compared to non-CB modified MCs@INS (5.15-fold), which was mainly attributed to the CB-mediated cell surface transporter via the PAT1 pathway. Moreover, the oral administration of CB-MCs@INS exhibited an excellent hypoglycaemic effect and maintained normoglycemia for up to 8 h in diabetic mice, demonstrating the great potential of crosslinked zwitterionic microcapsules as an oral insulin delivery platform for diabetes therapy.

Treatment of pyogenic liver abscess by surgical incision and drainage combined with platelet-rich plasma: A case report.

BACKGROUND: Pyogenic liver abscesses are insidious in the early stage. Some cases progress rapidly, and the patient's condition can worsen and even become life-threatening if timely treatment is not provided. Surgery and prolonged antibiotic treatment are often required if the abscess is large and liquefied and becomes separated within the lumen. CASE SUMMARY: We report a case of bacterial liver abscess with a poor outcome following pharmacological treatment, review the literature related to the use of platelet-rich plasma (PRP) in the treatment of hepatic impairment and partial hepatectomy in animals, and discuss the prognostic features of surgical incision and drainage combined with PRP in the treatment of bacterial liver abscesses. This is the first case describing the use of PRP in the treatment of a bacterial liver abscess in humans, providing new ideas for the treatment of this condition. CONCLUSION: This case highlights the importance of surgical treatment for bacterial liver abscesses that are well liquefied and poorly managed medically. PRP may produce antimicrobial effects and promote the regeneration and repair of liver tissue.

Residual Stress Redistribution Analysis in the Repair Welding of AA6082-T6 Aluminum Alloy Joints: Experiment and Simulation.

Residual stress has a three-dimensional scale effect (length, depth, and width) in the process of repair welding, which has a detrimental impact on the service of the aluminum alloy welded structures in high-speed trains. This paper aims to systematically analyze the effects of the repair welding dimension on the residual stress redistribution and obtain the optimal repair welding principles. A combination of blind-hole drilling method and stress linearization in BS7910 was adopted to investigate residual stress redistribution under various repair welding dimensions. The results indicate that repair welding dimension was in accordance with the principle of "SNL (shallow, narrow and long)" and the optimal repair length, depth, and width of butt joints in this study were 15t, 0.25t, and t, respectively (t is the plate thickness of butt joints).

Black Phosphorus-Synergic Nitric Oxide Nanogasholder Spatiotemporally Regulates Tumor Microenvironments for Self-Amplifying Immunotherapy.

The lack of tumor immunogenicity coupled with the presence of tumor immunosuppression severely hinders antitumor immunity, especially in the treatment of "immune cold" tumors. Here, we have developed a drug-free and NIR-enabled nitric oxide (NO)-releasing nanogasholder (NOPS@BP) composed of an outer cloak of nitrate-containing polymeric NO donor and an inner core of black phosphorus (BP) as the energy converter to spatiotemporally regulate NO-mediated tumor microenvironment remodeling and achieve multimodal therapy. Following NIR-irradiation, BP-induced photothermia and its intrinsic reducing property accelerate NO release from the outer cloak, by which the instantaneous NO burst concomitant with mild photothermia, on the one hand, induces immunogenic cell death (ICD), thereby provoking antitumor responses such as the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs); on the other hand, it reverses tumor immunosuppression via Treg inhibition, M2 macrophage restraint, and PD-L1 downregulation, further strengthening antitumor immunity. Therefore, this drug-free NOPS@BP by means of multimodal therapy (NO gas therapy, immune therapy, photothermal therapy) realizes extremely significant curative effects against primary and distant tumors and even metastasis in B16F10 tumor models, providing a new modality to conquer immune cold tumors by NO-potentiated ICD and immunosuppression reversal.

Recent advances on next generation of polyzwitterion-based nano-vectors for targeted drug delivery.

Poly (ethylene glycol) (PEG)-based nanomedicines are perplexed by the challenges of oxidation damage, immune responses after repeated injections, and limited excretion from the body. As an alternative to PEG, bioinspired zwitterions bearing an identical number of positive and negative ions, exhibit exceptional hydrophilicity, excellent biomimetic nature and chemical malleability, endowing zwitterionic nano-vectors with biocompatibility, non-fouling feature, extended blood circulation and multifunctionality. In this review, we innovatively classify zwitterionic nano-vectors into linear, hyperbranched, crosslinked, and hybrid nanoparticles according to different chemical architectures in rational design of zwitterionic nano-vectors for enhanced drug delivery with an emphasis on zwitterionic engineering innovations as alternatives of PEG-based nanomedicines. Through combination with other nanostrategies, the intelligent zwitterionic nano-vectors can orchestrate stealth and other biological functionalities together to improve the efficacy in the whole journey of drug delivery.

Cascade-Responsive Hierarchical Nanosystems for Multisite Specific Drug Exposure and Boosted Chemoimmunotherapy.

The precise delivery of multiple drugs to their distinct destinations plays a significant role in safe and efficient combination therapy; however, it is highly challenging to simultaneously realize the targets and overcome the intricate biological hindrances using an all-in-one nanosystem. Herein, a cascade-responsive hierarchical nanosystem containing checkpoint inhibitor anti-PD-L1 antibody (αPD-L1) and paclitaxel (PTX) is developed for spatially programed delivery of multiple drugs and simultaneously overcoming biological pathway barriers. The hierarchical nanoparticles (MPH-NP@A) are composed of pH-sensitive hyaluronic acid-acetal-PTX prodrugs (HA-ace-PTX(SH)) chaperoned by αPD-L1 and metalloproteinase-9 (MMP-9)-responsive outer shells, which could be fast cleaved to release αPD-L1 in the tumor microenvironment (TME). The released αPD-L1 sequentially synergizes with PTX released in the cytoplasm for boosted chemoimmunotherapy due to direct killing of PTX and intensified immune responses through immunogenic cell death (ICD) as well as suppression of immune escape by blocking the PD-1/PD-L1 axis. The in vitro and in vivo studies demonstrate that MPH-NP@A evokes distinct ICD, enhanced cytotoxic T lymphocytes infiltration, as well as significant tumor inhibition, thus providing a promising therapeutic nano-platform for safe and efficient combination therapy.

Multi-functional polymeric micelles for chemotherapy-based combined cancer therapy.

Currently, the therapeutic performance of traditional mono-chemotherapy on cancers remains unsatisfactory because of the tumor heterogeneity and multidrug resistance. In light of intricate tumor structures and distinct tumor microenvironments (TMEs), combinational therapeutic strategies with multiple anticancer drugs from different mechanisms can synergistically optimize the outcomes and concomitantly minimize the adverse effects during the therapy process. Extensive research on polymeric micelles (PMs) for biomedical applications has revealed the growing importance of nanomedicines for cancer therapy in the recent decade. Starting from traditional simple delivery systems, PMs have been extended to multi-faceted therapeutic strategies. Here we review and summarize the most recent advances in combinational therapy based on multifunctional PMs including a combination of multiple anticancer drugs, chemo-gene therapy, chemo-phototherapy and chemo-immunotherapy. The design approaches, action mechanisms and therapeutic applications of these nanodrugs are summarized. In addition, we highlight the opportunities and potential challenges associated with this promising field, which will provide new guidelines for advanced combinational cancer chemotherapy.