Acidic Microenvironment Research Articles

Detection of Residual Peritoneal Metastases Following Cytoreductive Surgery Using Pegsitacianine, a pH-Sensitive Imaging Agent: Final Results from a Phase II Study.

For patients with peritoneal carcinomatosis, extent of disease and completeness of cytoreductive surgery (CRS) are major prognostic factors for long-term survival. Assessment of these factors could be improved using imaging agents. Pegsitacianine is a pH-sensitive polymeric micelle conjugated to thefluorophore indocyanine green. The micelle disassembles in acidic microenvironments, such as tumors, resulting in localized fluorescence unmasking. We assessed the utility of pegsitacianine in detecting residual disease following CRS. NCT04950166 was a phase II, non-randomized, open-label, multicenter US study. Patients eligible for CRS were administered an intravenous dose of pegsitacianine at 1 mg/kg 24-72 h before surgery. Following CRS, the peritoneal cavity was reexamined under near-infrared (NIR) illumination to evaluate for fluorescent tissue. Fluorescent tissue identified was excised and evaluated by histopathology. The primary outcome was the rate of clinically significant events (CSE), defined as detection of histologically confirmed residual disease excised with pegsitacianine or a revision in the assessment of completeness of CRS. Secondary outcomes included acceptable safety and pegsitacianine performance. A total of 53 patients were screened, 50 enrolled, and 40 were evaluable for CSE across six primary tumor types. Residual disease was detected with pegsitacianine in 20 of 40 (50%) patients. Pegsitacianine showed high sensitivity and was well tolerated with no serious adverse events (SAEs). Transient treatment-related, non-anaphylactic infusion reactions occurred in 28% of patients. Pegsitacianine was well tolerated and facilitated the recognition of occult residual disease following CRS. The high rate of residual disease detected suggests that the use of pegsitacianine augmented surgeon assessment and performance during CRS.

Membrane-anchoring clickable Iridium(III) nanosonosensitizer in situ evokes PANoptosis for augmented tumor sono-immunotherapy

Developing activatable “off-on” sonosensitizers with superior sonodynamic activity and immunogenic cell death (ICD) induction ability is urgently needed for precise and boosted tumor sono-immunotherapy. Herein, a membrane-anchoring clickable Iridium(III) nanosonosensitizer is well-designed to elicit tumor-specific PANoptosis for enhanced sonodynamic therapy (SDT) and amplified immune activation. A click-activatable tetrazine-functionalized Iridium(III) sonosensitizer Tz-Ir with dual type I/II reactive oxygen species (ROS) generation ability is developed, and further encapsulated into crosslinked human serum albumin (HSA) to form acid-responsive nanosonosensitizer HSA@Tz-Ir. After tumor-targeting accumulation and acidic tumor microenvironment (TME)-triggered release, Tz-Ir can synchronously realize efficient click-activation and precise membrane-localization via specific bioorthogonal metabolic glycoengineering technology. Upon US irradiation, in situ activated Tz-Ir can generate abundant ROS to destroy tumor cell membrane for a high-efficiency SDT. Moreover, for the first time, the maximized membrane damage is certified to evoke highly immunogenic PANoptosis (pyroptosis, apoptosis and necroptosis) of tumor cells, resulting in remarkably amplified tumor immunogenicity. The PANoptosis-boosted ICD effect can elicit robust systemic adaptive and innate antitumor immunity to effectively inhibit the growths of primary/distant tumors and lung metastasis. This tumor-specific membrane-targeting SDT modality based on bioorthogonal click activation presents an innovative strategy for precise and augmented tumor sono-immunotherapy.

PH-Triggered Transformable Peptide Nanocarriers Extend Drug Retention for Breast Cancer Combination Therapy.

Increasing the penetration and accumulation of antitumor drugs at the tumor site are crucial in chemotherapy. Smaller drug-loaded nanoparticles (NPs) typically exhibit increased tumor penetration and more effective permeation through the nuclear membrane, whereas larger drug-loaded NPs show extended retention at the tumor site. In addition, cancer stem cells (CSCs) have unlimited proliferative potential and are crucial for the onset, progression, and metastasis of cancer. Therefore, a drug-loaded amphiphilic peptide, DDP- and ATRA-loaded Pep1 (DA/Pep1), is designed that self-assembles into spherical NPs upon the encapsulation of cis-diamminedichloroplatinum (DDP) and all-trans retinoic acid (ATRA). In an acidic environment, DA/Pep1 transforms into aggregates containing sheet-like structures, which significantly increases drug accumulation at the tumor site, thereby increasing antitumor effects and inhibiting metastasis. Moreover, although DDP treatment can increase the number of CSCs present, ATRA can induce the differentiation of CSCs in breast cancer to increase the therapeutic effect of DDP. In conclusion, this peptide nanodelivery system that transforms in response to the acidic tumor microenvironment is an extremely promising nanoplatform that suggests a new idea for the combined treatment of tumors.

Acidic solution irrigation as a novel approach for treating infected walled-off pancreatic necrosis

Walled-off pancreatic necrosis (WOPN) is a severe complication of acute pancreatitis arising from pancreatic or peripancreatic necrosis complicated by infection, leading to elevated mortality rates. Extravasation of pancreatic juice creates a weakly alkaline microenvironment favorable for the survivial of translocated intestinal bacteria and activated pancreatic enzyme-mediated autodigestion of pancreatic and peripancreatic tissues. Conventional treatments for WOPN involve invasive procedures with irrigation to mitigate postoperative infections. However, there remains a lack of a unified standard for lavage fluid. Herein, we raise the hypothesis that the utilization of acidic solution irrigation may serve as a promising strategy for preventing and treating infected WOPN. Acidic solutions create an unfavorable environment for translocated intestinal bacteria in WOPN cases. Additionally, the acidic microenvironment may alleviate self-digestion of pancreatic and peripancreatic tissues by inhibiting pancreatic enzyme activity. This innovative approach holds potential for enhancing the management and outcomes of infected WOPN.

Targeted acidosis mediated delivery of antigenic MHC-binding peptides.

Cytotoxic T lymphocytes are the primary effector immune cells responsible for protection against cancer, as they target peptide neoantigens presented through the major histocompatibility complex (MHC) on cancer cells, leading to cell death. Targeting peptide-MHC (pMHC) complex offers a promising strategy for immunotherapy due to their specificity and effectiveness against cancer. In this work, we exploit the acidic tumor micro-environment to selectively deliver antigenic peptides to cancer using pH(low) insertion peptides (pHLIP). We demonstrated the delivery of MHC binding peptides directly to the cytoplasm of melanoma cells resulted in the presentation of antigenic peptides on MHC, and activation of T cells. This work highlights the potential of pHLIP as a vehicle for the targeted delivery of antigenic peptides and its presentation via MHC-bound complexes on cancer cell surface for activation of T cells with implications for enhancing anti-cancer immunotherapy.

Nucleus-targeting DNase I self-assembly delivery system guided by pirarubicin for programmed multi-drugs release and combined anticancer therapy

The cell nucleus serves as the pivotal command center of living cells, and delivering therapeutic agents directly into the nucleus can result in highly efficient anti-tumor eradication of cancer cells. However, nucleus-targeting drug delivery is very difficult due to the presence of numerous biological barriers. Here, three antitumor drugs (DNase I, ICG: indocyanine green, and THP: pirarubicin) were sequentially triggered protein self-assembly to produce a nucleus-targeting and programmed responsive multi-drugs delivery system (DIT). DIT consisted of uniform spherical particles with a size of 282 ± 7.7 nm. The acidic microenvironment of tumors and near-infrared light could successively trigger DIT for the programmed release of three drugs, enabling targeted delivery to the tumor. THP served as a nucleus-guiding molecule and a chemotherapy drug. Through THP-guided DIT, DNase I was successfully delivered to the nucleus of tumor cells and killed them by degrading their DNA. Tumor acidic microenvironment had the ability to induce DIT, leading to the aggregation of sufficient ICG in the tumor tissues. This provided an opportunity for the photothermal therapy of ICG. Hence, three drugs were cleverly combined using a simple method to achieve multi-drugs targeted delivery and highly effective combined anticancer therapy.

Biofilm of petroleum-based and bio-based microplastics in seawater in response to Zn(II): Biofilm formation, community structure, and microbial function

Microplastic biofilms are novel vectors for the transport and spread of pathogenic and drug-resistant bacteria. With the increasing use of bio-based plastics, there is an urgent need to investigate the microbial colonization characteristics of these materials in seawater, particularly in comparison with conventional petroleum-based plastics. Furthermore, the effect of co-occurring contaminants, such as heavy metals, on the formation of microplastic biofilms and bacterial communities remains unclear. In this study, we compared the biofilm bacterial community structure of petroleum-based polyethylene (PE) and bio-based polylactic acid (PLA) in seawater under the influence of zinc ions (Zn2+). Our findings indicate that the biofilm on PLA microplastics in the late stage was impeded by the formation of a mildly acidic microenvironment resulting from the hydrolysis of the ester group on PLA. The PE surface had higher bacterial abundance and diversity, with a more intricate symbiotic pattern. The bacterial structures on the two types of microplastics were different; PE was more conducive to the colonization of anaerobic bacteria, whereas PLA was more favorable for the colonization of aerobic and acid-tolerant species. Furthermore, Zn increased the proportion of the dominant genera that could utilize microplastics as a carbon source, such as Alcanivorax and Nitratireductor. PLA had a greater propensity to harbor and disseminate pathogenic and drug-resistant bacteria, and Zn promoted the enrichment and spread of harmful bacteria such as, Pseudomonas and Clostridioides. Therefore, further research is essential to fully understand the potential environmental effects of bio-based microplastics and the role of heavy metals in the dynamics of bacterial colonization.

Sprayable and self-healing chitosan-based hydrogels for promoting healing of infected wound via anti-bacteria, anti-inflammation and angiogenesis

Treatment of infected wound by simultaneously eliminating bacteria and inducing angiogenesis to promote wound tissue regeneration remains a clinical challenge. Dynamic and reversable hydrogels can adapt to irregular wound beds, which have raised great attention as wound dressings. Herein, a sprayable chitosan-based hydrogel (HPC/CCS/ODex-IGF1) was developed using hydroxypropyl chitosan (HPC), caffeic acid functionalized chitosan (CCS), oxidized dextran (ODex) to crosslink through the dynamic imine bond, which was pH-responsive to the acidic microenvironment and could controllably release insulin growth factor-1 (IGF1). The HPC/CCS/ODex-IGF1 hydrogels not only showed self-healing, self-adaptable and sprayable properties, but also exhibited excellent antibacterial ability, antioxidant property, low-cytotoxicity and angiogenetic activity. In vivo experiments demonstrated that hydrogels promoted tissue regeneration and healing of bacteria-infected wound with a rate of approximately 98.4 % on day 11 by eliminating bacteria, reducing inflammatory and facilitating angiogenesis, demonstrating its great potential for wound dressing.

Interfering tumor metabolism by bimetallic nanoagent for amplifying nanocatalytic-mediated glioblastoma immunotherapy

Glioblastoma is a malignant tumor with a high recurrence rate and a profound immunosuppressive microenvironment that makes immunotherapy ineffective. Herein, an iron-copper bimetallic nanoagent (NMCuA) grafted with blood–brain barrier (BBB) cells targeting peptide angiopep-2 and loaded indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor (NLG919) for remodulating the immunosuppressive microenvironment to enhance the therapeutic efficiency of glioblastoma immunotherapy is demonstrated. Such NMCuA can synergistically amplify nanocatalytic-mediated glioblastoma immunotherapy by interfering with amino acid metabolism. Briefly, Cu/Fe released from the nanoagent undergoes a catalytic reaction to generate cytotoxic hydroxyl radicals (•OH) in the acidic tumor microenvironment (TME), leading to intracellular lipid peroxidation (LPO). Meanwhile, Cu2+ also chelates with excess cysteine (Cys), resulting in glutathione (GSH) depletion and glutathione peroxidase 4 (GPX4) inactivation, further promoting LPO accumulation. In addition, IDO1-mediated tryptophan metabolic pathway is inhibited by NLG919, thus contributing to the reduction of Treg cells (Tregs) accumulation and •OH clearance. Therefore, interfering tumor metabolism enhances metal-based catalytic therapy, which further strengthens •OH burst and intracellular LPO accumulation, thereby triggering an effective immunogenic cell death (ICD) process. This bimetallic nanoagent activates the body to generate a powerful immune response that can significantly inhibit in situ tumor growth and reversing the immunosuppressive TME. Furthermore, the nanoagent can generate effective immune memory effects by combining immune checkpoint inhibitor, thereby suppressing glioblastoma recurrence.

Reactive Microneedle Patches with Antibacterial and Dead Bacteria-Trapping Abilities for Skin Infection Treatment.

Bacterial skin infections are highly prevalent and pose a significant public health threat. Current strategies are primarily focused on the inhibition of bacterial activation while disregarding the excessive inflammation induced by dead bacteria remaining in the body and the effect of the acidic microenvironment during therapy. In this study, a novel dual-functional MgB2 microparticles integrated microneedle (MgB2 MN) patch is presented to kill bacteria and eliminate dead bacteria for skin infection management. The MgB2 microparticles not only can produce a local alkaline microenvironment to promote the proliferation and migration of fibroblasts and keratinocytes, but also achieve >5 log bacterial inactivation. Besides, the MgB2 microparticles effectively mitigate dead bacteria-induced inflammation through interaction with lipopolysaccharide (LPS). With the incorporation of these MgB2 microparticles, the resultant MgB2 MN patches effectively kill bacteria and capture dead bacteria, thereby mitigating these bacteria-induced inflammation. Therefore, the MgB2 MN patches show good therapeutic efficacy in managing animal bacterial skin infections, including abscesses and wounds. These results indicate that reactive metal borides-integrated microneedle patches hold great promise for the treatment of clinical skin infections.

Abstract LB425: A tumor microenvironment-targeting CD98-directed ADC confers robust anti-tumor activity in multiple cancers with favorable pharmacokinetics and safety profiles in preclinical models

Abstract CD98, a subunit of the LAT1/CD98 amino acid transporter complex, is intimately involved in cell adhesion, migration, proliferation, and signal transduction by enhancing amino acid transport and amplifying integrin signaling. CD98 is expressed at aberrantly high levels in many solid tumors and hematological malignancies, and this is frequently associated with poor prognosis, highlighting its potential as a cancer therapy target. However, CD98 is also expressed in various normal tissues hence complicating the development of antibody-based therapies owing to lack of tumor selectivity, poor pharmacokinetics (PK), and safety issues. We previously reported a pH-dependent anti-CD98 monoclonal antibody (mAb) that selectively targets the acidic tumor microenvironment (Tian, X., et al. Nat Biomed Eng 7(1): 8-23.). In the present report, we further developed that mAb into an antibody-drug conjugate (ADC; HH018-sesutecan), in which the mAb is conjugated to a topoisomerase I inhibitor-based linker-drug, sesutecan, at a drug:antibody ratio (DAR) of approximately 8. Sesutecan previously demonstrated promising characteristics in preclinical studies with multiple targets and conferred an encouraging benefit:risk profile in the clinic with a FRα-directed ADC (rinatabart sesutecan). HH018-sesutecan exhibited similar pH-dependent binding as its parental mAb in vitro, and markedly improved PK compared to the non-pH-dependent ADC control in CD98-humanized C57BL/6 mice. HH018-sesutecan demonstrated potent cytotoxicity against CD98-expressing cancer cell lines, strong bystander effect, as well as dose-dependent anti-tumor activity in mouse models representing multiple tumor types (colorectal cancer, ovarian cancer, renal cell carcinoma, lymphoma, hypopharyngeal carcinoma, and oral adeno-squamous carcinoma). Notably, sustained tumor regression was achieved with a single dose of 3-5 mg/kg in ~8 tumor models. A pilot toxicity study was conducted for HH018-sesutecan at two repeat-dose of 30 mg/kg in cynomolgus monkeys. HH018-sesutecan was well-tolerated with the principal toxicity (myelosuppression) being payload driven and reversible, accompanied with a favorable PK profile (half-life of 7-9 days). In summary, our studies demonstrate that the pH-dependent CD98-directed HH018- sesutecan exerts wide-ranging and potent anti-tumor efficacy, as well as favorable PK and safety profiles in preclinical models. HH018-sesutecan is a promising agent for further development in a broad range of CD98-expressing tumors. Citation Format: Fang Yang, Lei Wang, Xinxin Tian, Xuan Qiu, Jianhe Chen, Wenke Qi, Guangyu Li, Haidong Liu, Juan Liu, Suping Huang, Bin Ye, Qilin Wu, Baiteng Zhao, Wenhui Li, Jianhua Sui, Zhu Chen. A tumor microenvironment-targeting CD98-directed ADC confers robust anti-tumor activity in multiple cancers with favorable pharmacokinetics and safety profiles in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB425.

A Microfluidics-Assisted Double-Barreled Nanobioconjugate Synthesis Introducing Aprotinin as a New Moonlight Nanocarrier Protein: Tested toward Physiologically Relevant 3D-Spheroid Models.

Proteins are promising substances for introducing new drug carriers with efficient blood circulation due to low possibilities of clearance by macrophages. However, such natural biopolymers have highly sophisticated molecular structures, preventing them from being assembled into nanoplatforms with manipulable payload release profiles. Here, we report a novel anticancer nanodrug carrier moonlighting protein, Aprotinin, to be used as a newly identified carrier for cytotoxic drugs. The Aprotinin-Doxorubicin (Apr-Dox) nanobioconjugate was prepared via a single-step microfluidics coflow mixing technique, a feasible and simple way to synthesize a carrier-based drug design with a double-barreled approach that can release and actuate two therapeutic agents simultaneously, i.e., Apr-Dox in 1:11 ratio (the antimetastatic carrier drug aprotinin and the chemotherapeutic drug DOX). With a significant stimuli-sensitive (i.e., pH) drug release ability, this nanobioconjugate achieves superior bioperformances, including high cellular uptake, efficient tumor penetration, and accumulation into the acidic tumor microenvironment, besides inhibiting further tumor growth by halting the urokinase plasminogen activator (uPA) involved in metastasis and tumor progression. Distinctly, in healthy human umbilical vein endothelial (HUVEC) cells, drastically lower cellular uptake of nanobioconjugates has been observed and validated compared to the anticancer agent Dox. Our findings demonstrate an enhanced cellular internalization of nanobioconjugates toward breast cancer, prostate cancer, and lung cancer both in vitro and in physiologically relevant biological 3D-spheroid models. Consequently, the designed nanobioconjugate shows a high potential for targeted drug delivery via a natural and biocompatible moonlighting protein, thus opening a new avenue for proving aprotinin in cancer therapy as both an antimetastatic and a drug-carrying agent.

PH-responsive self-assembling peptides potentiate therapeutic efficacy via prolonged drug retention and immunomodulation

Insufficient drug accumulation at tumor sites is one of the key factors leading to treatment failure in breast cancer (BC), and developing a chemotherapeutic drug delivery system that can improve the immune microenvironment to expand the benefits of immunochemotherapy for BC remains a challenge. To increase the efficacy of BC treatment by extending drug retention at the tumor site, we developed a pH-responsive peptide modified with the PHSCN peptide sequence (Pep1) that self-assembles to form spherical DM/Pep1 nanoparticles after encapsulating doxorubicin (DOX) and metformin (MET). In the acidic tumor microenvironment, spherical nanocarriers transform into aggregates with a high aspect ratio, facilitating DOX and MET release for combined chemotherapy and immunomodulation. In cellular experiments, this construct provided prolonged drug retention in BC cells. In a subcutaneous tumor mouse model, the DM/Pep1 nanoparticles exhibited a superior tumor inhibition effect compared to that of free DOX/MET. The DM/Pep1 nanocomplex upregulated CD4, induced calreticulin (CRT) exposure, downregulated PD-L1, and enhanced the MET-mediated antitumor immune response. The use of this pH-responsive peptide nanocarrier system with morphological transformation offers a promising strategy for BC therapy.

PEGylated graphene oxide-mediated stimulation of vascular endothelial cells and responsive release of PD-1/PD-L1 inhibitor for efficient chemo-immunotherapy against cancer

Immune checkpoint blockade (ICB) has emerged as a promising immunotherapeutic modality against cancer in the clinic. However, only 10–30% of patients respond to ICB, primarily due to poor immunogenicity and insufficient T cell infiltration in solid tumors. Herein, we presented an approach for high-performance cancer treatment using the programmed cell death protein-1 and programmed cell death ligand-1 (PD-1/PD-L1) inhibitor (BMS-202)-loaded PEGylated graphene oxide (GPi). On the one hand, GPi dissociated tight junctions of vascular endothelial cells (VECs) in tumor, thus promoting the extravasation and intratumoral accumulation of liposomal doxorubicin (LipDox), which then effectively induced immunogenic cell death of tumor cells. On the other hand, GPi also stimulated VECs to upregulate the expression of cell-cell interaction molecules, such as intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, which facilitated the infiltration of T cells in tumor. Beyond acting as a stimulator of VECs, GPi could exert responsive release of BMS-202 under the acidic tumor microenvironment and blockade PD-1/PD-L1 axis in tumors. Finally, the alternating administration of GPi and LipDox effectively inhibited tumor growth in a 4T1 tumor model, providing a novel treatment mode for chemo-immunotherapy.

Deciphering the interaction mechanism between soy protein isolate and fat-soluble anthocyanin on experiments and molecular simulations

In this work, the acylated anthocyanin (Ca-An) was prepared by enzymatic modification of black rice anthocyanin with caffeic acid, and the binding mechanism of Ca-An to soybean protein isolate (SPI) was investigated by experiments and computer simulation to expand the potential application of anthocyanin in food industry. Multi-spectroscopic studies revealed that the stable binding of Ca-An to SPI induced the folding of protein polypeptide chain, which transformed the secondary structure of SPI trended to be flexible. The microenvironment of protein was transformed from hydrophobic to hydrophilic, while tyrosine played dominant role in quenching process. The binding sites and forces of the complexes were determined by computer simulation for further explored. The protein conformation of the 7S and 11S binding regions to Ca-An changed, and the amino acid microenvironment shifted to hydrophilic after binding. The results showed that more non-polar amino acids existed in the binding sites, while in binding process van der Waals forces and hydrogen bonding played a major role hydrophobicity played a minor role. Based on MM-PBSA analysis, the binding constants of 7S-Ca-An and 11S-Ca-An were 0.518 × 106 mol−1 and 5.437 × 10−3 mol−1, respectively. This information provides theoretical guidance for further studying the interaction between modified anthocyanins and biomacromolecules.

An investigation of the binding of two cinnamate UV filters to bovine serum albumin separately and simultaneously

A study of the separate/simultaneous interaction mechanism between two common cinnamate ultraviolet filters (UVFs), Octtocrylene (OC) and 2-ethylhexyl 4-methoxycinnamate (EHMC), with bovine serum albumin (BSA) was conducted. Both OC and EM can bind to BSA. A more obvious fluorescence quenching effect was observed with EHMC on BSA, as well as a stronger affinity for BSA and a greater effect on the amino acid microenvironment. UVFs and BSA's binding constants were decreased when EHMC and OC interacted simultaneously with BSA, while the distance between UVFs and BSA was increased. Coexistence affected both OC and EHMC, making them less able to binding to BSA. While binding simultaneously to EHMC and OC, BSA's secondary structure underwent significant changes.

Hydrolysis of Cellulose Acetate Phthalate and Hydroxypropyl Methylcellulose Phthalate in Amorphous Solid Dispersions

The preparation of amorphous solid dispersions (ASDs) represents a promising strategy for addressing the solubility limitations of poorly soluble drugs, facilitating enhanced absorption. Acidic polymers such as cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HPMCP) have emerged as effective carriers for ASDs. Although the hydrolytic degradation of these polymers has been documented, its impact on the stability of ASDs has not been systematically investigated. This research aimed to explore the potential hydrolysis of CAP and HPMCP and how it influences the stability of ASDs containing ketoconazole (KTZ), at drug loadings of 10 % and 50 %. Our study utilized thermal analysis, infrared spectroscopy, and evaluations of physical and chemical stability. The results revealed that although KTZ remained physically stable in all ASDs over a 60-day period under various stability conditions, the emergence of crystalline phthalic acid (PA), a byproduct of polymer hydrolysis, was observed at elevated temperatures and relative humidity levels. The acidic microenvironment fostered by the release of PA further catalyzed drug chemical degradation. This study underscores the susceptibility of CAP and HPMCP to hydrolytic degradation, highlighting the inherent risk of PA-induced drug degradation, particularly for acid-labile compounds. These insights into the understanding of polymer hydrolysis in ASDs pave the way for the development of targeted approaches to safeguard drug stability and optimize pharmaceutical formulations for enhanced bioavailability, efficacy, and safety.

Fabrication of pH-responsive nanoparticles for co-delivery of fungicide and salicylic acid with synergistic antifungal activity

Stimuli-responsive co-delivery nanopesticides with different action mechanisms have received widespread attention due to the improved bioactivity, long effective duration, and reduced risks to the environment. Herein, fungicide tebuconazole (TEB) and plant immune inducer poly(salicylic acid) (PSA) co-assembled nanoparticles (TP NPs) are fabricated through non-covalent interactions without the use of any adjuvants. The results show that the obtained TP NPs have excellent physicochemical properties, displaying uniform morphology with an average particle size of 152 nm, low PDI (0.064), and high surface activity. The TP NPs exhibit acid-responsive behaviors, enabling the intelligent release of active ingredients in the specific acidic microenvironment caused by the invasion of plant pathogens. In vitro fungicidal activities of TP NPs are 1.9 and 1.6 times higher than TEB technical against Sclerotinia sclerotiorum and Fusarium graminearum respectively. Additionally, the stimuli-responsive co-delivery fungicidal nanosystem not only has a longer effective duration compared to both TEB technical and TP Mix but also significantly reduces the genetic toxicity of TEB to the plants. Therefore, this fungicide and plant immune inducer co-delivery nanosystem provides a novel strategy for development of multimode synergetic nanopesticide and sustainable plant disease management.

Yeast‐Controlled Double‐Shelled CaCO3/CaF2 Hollow Nanospheres with Hierarchically Porous for Sustained pH‐Sensitive Drug Release

Comprehensive SummaryHierarchically porous materials (HP materials) are believed one of the most hopeful matrix materials because of their distinctive multimodal pore structures and tremendous application potentials in the field of biomedicine. However, green and facile synthesis of hierarchically porous nanomaterials with beneficial water dispersibility and biocompatibility is still a great challenge. Herein, a novel biomimetic strategy is proposed to prepare the cell‐tailored double‐shelled HPCaCO3/CaF2 hollow nanospheres under the mediation of yeast cells. The biomolecules derived from the secretion of yeast cells are used as conditioning and stabilizing agents to control the biosynthesis of the HPCaCO3/CaF2 materials, which exhibit excellent water dispersibility and favorable biocompatibility. The double‐shelled CaCO3/CaF2 nanospheres hold hierarchically porous structure and have abundant pore channel and large specific surface area, showing high drug‐loading and a prolonged drug sustainable release profile by the pore‐by‐pore diffusion pattern of the hierarchical pores. Otherwise, the HPCaCO3 with pH‐sensitivity could controllably release drug doxorubicin hydrochloride (DOX) at the acidic tumor microenvironment. Both in vitro and in vivo results demonstrate that HPCaCO3/CaF2 has the sustainable pH‐sensitive drug release property, showing an enhanced therapeutic effect. Summarily, this study provides a biomimetic strategy to synthesize the hierarchically porous double‐shelled hollow nanomaterials for applying in sustainable drug delivery system.

Tumor microenvironment responsive multifunctional smart living materials based on engineered bacteria for inducing macrophage polarization to enhance tumor immunotherapy

The utilization of bacteria as a drug delivery system represents a promising strategy for tumor therapy, owing to their inherent ability to selectively colonize and induce apoptosis of tumor cells at the solid tumor. However, the occurrence of dose-dependent toxicity has led to the failure of clinical trials. Unfortunately, the implementation of a singular bacterial treatment strategy for tumor therapy is inherently limited. In this study, we developed a living drug delivery material named DOX@TA@ECN (D@T@E) by utilizing Fe3+ and tannin acid (TA) as a cross-linking network to encapsulate doxorubicin (DOX) and form a protective coating on the surface of Escherichia coli Nissle 1917 (ECN). In an acidic tumor microenvironment, D@T@E disintegrated the coating to release DOX through the highly expressed H2O2. To enhance biosafety, the D@T@E was equipped with a hypoxic lytic circuit (Pvhb-Lysis) to regulate the number of ECN in vivo (D@T@E-PL). The hypoxic promotor of Vitreoscilla hemoglobin protein (Pvhb) were activied to induce expression of lysis protein (PhiX174E) in the tumor hypoxic microenvironment (3 %), resulting in ECN lysis and subsequent elimination by the immune system. Additionally, D@T@E-PL pass lysis to release relevant antigens (DNA and flagellin). This antigen promotes the polarization of M2-type tumor-promoting macrophages towards M1-type anti-tumor macrophages at the tumor microenvironment by activating Toll-like receptor 4 (TLR4), eliciting immune-mediated anti-tumor responses. The in vivo findings demonstrated that D@T@E-PL intelligent material demonstrated enhanced biosecurity through the lytic circuit and effectively suppressed tumor growth, thereby achieving a dual therapeutic approach combining chemotherapy and immunotherapy for tumor inhibition.