Tumor immunotherapy is often compromised by an immunosuppressive tumor microenvironment (TME) characterized by abnormal vasculature and exhausted T cells. Here, given the role of nitric oxide (NO) in favorably remodeling the TME, we engineered Escherichia coli Nissle 1917 (ECN) with a synthetic arginine-NO circuit (ECN-NO) that modifies the arginine synthesis pathway to constitutively synthesize arginine and enable sustained NO production. Specifically, deletion of the arginine repressor ArgR relieved feedback inhibition of arginine biosynthesis, whereas co-expression of argininosuccinate synthase and lyase (ArgG/ArgH), together with Bacillus subtilis nitric oxide synthase (BsNOS), enabled sustained NO production through enhanced arginine regeneration. Intratumoral colonization of ECN-NO significantly enhanced the antitumor efficacy of anti-programmed cell death ligand 1 (αPD-L1) immunotherapy, resulting in durable tumor regression across multiple solid tumor mouse models. Mechanistically, ECN-NO induced vascular normalization and dendritic cell recruitment, alleviated tumor immunosuppression and synergized with αPD-L1 to expand functional CD8+ T cells, reverse T cell exhaustion and promote memory T cell formation, establishing antitumor immunity for at least 120 days.

Bladder cancer (BC) is a common malignancy, yet conventional white light cystoscopy (WLC) has suboptimal diagnostic accuracy. Nectin4, a membrane protein highly expressed in BC, is an attractive molecular imaging target. By conjugating indocyanine green (ICG) to enfortumab vedotin, we develop NECTIN4-ICG, a BC-specific fluorescence imaging probe. In BC mouse models, NECTIN4-ICG enables targeted detection and doubles the complete tumor resection rate. In an ex vivo study of 18 fresh human bladders yielding 82 specimens, NECTIN4-ICG-guided biopsy achieves 96.3% diagnostic accuracy. In a clinical trial involving 20 patients yielding 198 specimens, NECTIN4-ICG-guided biopsy achieves 96.0% diagnostic accuracy and 91.1% tumor margin detection, outperforming WLC (82.2% and 73.3%). NECTIN4-ICG also enables fluorescence-guided TURBT, enhancing real-time visualization, margin assessment, and carcinoma in situ detection with a favorable safety profile. This clinical trial is registered under ChiCTR2200067094 and ChiCTR2400092677.

Immunotherapy shows promise for triple-negative breast cancer (TNBC), yet its effectiveness is restricted by low response rates, poor immune cell infiltration, and systemic side effects. Here, an ultrasound-responsive cerasomal nanoplatform integrating a STING agonist (SR-717@PC-iRGD) is developed for synergistic sonodynamic-immunotherapy. The nanocarrier is self-assembled from cerasome-forming lipids (CFL), porphyrin-conjugated lipids (PL), unsaturated phospholipids (DOPC), DSPC, and DSPE-PEG2000-iRGD, with SR-717 loaded in the lipid bilayer. The resulting assembly yields nanoparticles (NPs) with high SR-717 loading and exceptional stability. The siloxane shell (cerasome) confers high stability and prevents premature drug leakage, while iRGD promotes nanoparticle binding to tumor specific integrin to facilitate accumulation and retention in the tumor. Upon ultrasound irradiation, porphyrin generates reactive oxygen species (ROS) that oxidize the lipid bilayer and disrupt the cerasome, enabling on-demand SR-717 release at tumor site. The released SR-717 activates the STING pathway, driving type-I interferon production, dendritic cell maturation, and CD8+ T-cell infiltration. This strategy integrates sonodynamic therapy (SDT) with localized immune activation, addressing challenges of instability and inefficient delivery. The platform thus offers a precise and effective approach to stimulate antitumor immunity and enhance therapeutic outcomes for TNBC where no tumor targeted therapy is currently available.

Pancreatic ductal adenocarcinoma (PDAC) exhibits limited responsiveness to immunotherapy, primarily due to its dense stromal barrier, a lactate-rich immunosuppressive microenvironment, and impaired antigen-presenting function of dendritic cells (DCs). To address these challenges, we developed an ultrasound-responsive piezoelectric nanoplatform, BPF@L-S, designed to simultaneously overcome tumor delivery barriers, remodel lactate metabolism, and activate DCs-mediated antitumor immunity. Upon ultrasound stimulation, BaTiO₃ (BTO) generates piezoelectric effects and reactive oxygen species (ROS)-mediated stress responses, which not only enhance tumor cell damage and induce immunogenic cell death but also trigger localized bioelectric–ionic signaling and Ca2+ flux perturbations, promoting the restoration of DCs maturation and T cell effector function. Concurrently, lactate dehydrogenase (LDH) inhibition reduces lactate production, alleviating lactate-induced acidosis, oxidative stress, and immune suppression, while decreasing tumor cell resistance to oxidative stress. By integrating an optimized delivery system, lactate metabolic reprogramming, piezoelectric therapy, and immune activation, BPF@L-S effectively overcomes the dual barriers of dense stroma and metabolic immunosuppression in PDAC, enhancing DCs uptake, maturation, and cross-presentation of antigens, thereby potentiating T cell-mediated antitumor immunity and significantly improving PDAC sensitivity to immunotherapy. This study proposes a novel strategy that combines piezoelectric nanotherapy with immunometabolic modulation for the treatment of PDAC.

Sonodynamic therapy (SDT) is a promising non-invasive modality for cancer treatment, leveraging ultrasound to activate therapeutic agents deep within tissues. However, its clinical translation has been hampered by inefficient reactive oxygen species (ROS) generation, limited tumor-specific accumulation, and poor penetration across biological barriers such as the blood-tumor barrier (BTB). To address these challenges, we engineered ultrasmall core-shell nanosonosensitizers composed of porphyrin-grafted lipids (PGL) encapsulating gold nanoparticles (AuNPs), and further functionalized them with the tumor-homing peptide CREKA (Cys-Arg-GluLys-Ala), forming Au@PGL-CREKA (APC) nanoparticles. The sub-10 nm size of APC facilitates effective traversal of physiological barriers and deep tumor penetration. The gold core synergistically enhances the sonodynamic activity of porphyrins, significantly boosting ROS production under ultrasound irradiation. Targeting via CREKA improves selective tumor accumulation while reducing hepatic uptake, thereby increasing extrahepatic delivery. In a U87 solid tumor mouse model, APC SDT treatment with low-intensity focused ultrasound (LIFU) led to pronounced tumor regression and minimal off-target toxicity. These findings underscore the potential of APC as a targeted, deep-penetrating, and highly efficient sonosensitizer platform for treating aggressive solid tumors such as glioblastoma (GBM).

This Highlight describes a key observation where serotonin transporter (SERT) was shown to suppress CD8+ T cell antitumor responses via depletion of intratumoral 5-HT. While selective serotonin reuptake inhibitors (SSRIs)—among the most widely used antidepressants—significantly inhibit tumor growth and enhance T cell-mediated antitumor immunity in both mouse models and human xenografts, showing remarkable synergy with anti-PD-1 therapy. These findings emphasize the importance of intratumoral 5-HT signaling, establish SERT as an immune checkpoint, and identify SSRIs as promising candidates for cancer immunotherapy.

Diabetic wound (DW) is a diabetes complication characterized by high morbidity and disability rates. Previous therapeutic systems focused on macrophages while neglecting the upstream regulatory factor of neuropeptide-mediated neuroimmune communication. In addition, precise delivery is directly important for the treatment of DW. This study constructed an amphiphilic prodrug molecule MC by covalently conjugating calcitonin gene-related peptide (CGRP) with manganese porphyrin (MnP). MC was then co-assembled with DSPE-PEG-folic acid to form targeted nanoparticles MCF. Subsequently, MCF was loaded into an ultrasound-responsive hydrogel to obtain the MCF@CA system, integrating neuroimmune modulation and reactive oxygen species (ROS) scavenging functions. Upon local administration, ultrasound triggering enables the on-demand release of the nanodrug MCF from MCF@CA. Subsequently, FA targets M1 macrophages, prolonging wound retention time. MnP scavenges ROS, improving fibroblast function and promoting macrophage polarization towards an anti-inflammatory phenotype. This study presents an ultrasound-responsive hydrogel MCF@CA delivering targeted nanoparticles where CGRP regulates the regenerative transition of the immune microenvironment. Animal experiments confirmed that MCF@CA combined with ultrasound significantly promotes DW healing by enhancing collagen deposition, immune modulation, and improving blood supply. Therefore, this study provides an on-demand controlled delivery platform with clear translational potential for diabetic wound therapy.

The immunosuppressive tumor microenvironment of ovarian cancer renders it insensitive to immunotherapy. Current immunotherapy strategies, like immune checkpoint inhibitors (ICIs), only focus on “single-point interventions” targeting specific parts of the antitumor immune cycle, but lack systematic coordination throughout the cycle, which shows low therapeutic effect. In this study, we develop an ultrasound-mediated, dendritic cell membrane-driven multifunctional immunotherapy platform (aDCM@mPEG-TK/MSN-DOX-Ce6), comprising a mesoporous silica nanoparticle (MSN) loaded with the chemotherapeutic drug doxorubicin (DOX) and the sonosensitizer Chlorine e6 (Ce6) as the “core”; reactive oxygen species (ROS)-responsive thioketal grafted methoxy polyethylene glycol (mPEG-TK) serving as the “gatekeeper”, and an activated dendritic cell membrane (aDCM) as the “shell”. The antigen peptide-MHC molecules and co-stimulatory molecules CD80/CD86 on the surface of aDCM provide the first and second signals for naive T cell activation and directly initiate the antitumor immune cycle. Targeted chemotherapy synergizing with sonodynamic therapy (SDT) induces potent immunogenic cell death (ICD), releasing a large amount of tumor antigens as sustained, abundant “antigen fuel” to support the restart and positive feedback self-maintenance of the immune cycle. This multifunctional nanoplatform activates local and systemic antitumor immune responses, effectively transforming the “cold” tumor into the “hot” tumor, thereby enhancing ovarian cancer sensitivity to ICIs. Simultaneously, it promotes the generation of memory T cell populations, achieving sustained immune surveillance and memory. This combined immunotherapy nanoplatform represents a significant shift from “single-point intervention” to “systemic regulation”, offering a novel approach for efficient tumor immunotherapy of ovarian cancer.

BACKGROUND:Conventional age <50 versus ≥50 years grouping may obscure colorectal cancer (CRC) burden patterns around the contemporary screening boundary. We examined whether adults aged 45-49 years occupy a threshold-adjacent position not captured by conventional grouping. METHODS:Using GBD 2023 data, we analyzed CRC incidence, deaths, and DALYs from 1990 to 2023 across four age groups (15-44, 45-49, 50-74, 75+ years). We assessed global and SDI-stratified trends, inequality, empirical lower-bound burden frontiers, and decomposition of burden change. Sensitivity analyses included conventional age regrouping, High versus Non-High SDI decomposition, split-period analyses, and adjacent 5-year age-group comparisons. RESULTS:Incidence rose most in adults aged 15-44 (+16.8%) and 45-49 years (+11.0%), with smaller increases in those aged 50-74 (+7.5%) and 75+ (+3.6%). Deaths and DALYs declined more clearly above age 50. In adults aged 45-49, incidence inequality remained positive but narrowed (CI: 0.304 to 0.253; relative SII: 1.693 to 1.412), while DALY inequality weakened (CI: 0.159 to 0.068). During 2010-2023, the residual rate-change component contributed positively to incidence in adults aged 45-49 globally (31.5%) but was slightly negative in those aged 50-74 (-2.6%). Post-2018 amplification in High-SDI populations was consistent with screening-related detection effects. CONCLUSIONS:Adults aged 45-49 occupy a context-dependent threshold-adjacent position in global CRC burden redistribution. These findings inform population-level surveillance and policy evaluation rather than individual-level clinical decision-making.

Piezocatalytic process presents an effective alternative to photocatalysis for antibacterial treatment due to their degradation efficiency and tissue penetration; however, the necessity for a non-centrosymmetric structure and the prevalence of lead-based materials poses challenges. Therefore, it is essential to develop lead-free and highly efficient piezocatalytic materials to effectively kill bacteria. Herein, we propose a doping engineering design approach to achieve piezoelectric effect and improve the ROS quantum yield by introducing iron hard ferromagnetic element into spinel-phase zinc stannate (Zn2SnO4, ZTO) host matrix. Notably, a 5

Cuproptosis-based cancer immunotherapy is severely limited by hypoxia-associated metabolic resistance, immunosuppressive tumor microenvironments, and the lack of tumor-selective delivery of cuproptosis inducers. Herein, we developed a temporally coordinated therapeutic strategy by integrating a tumor-targeting nitric oxide (NO)-producing bacterial platform (ECN-NO) with ultrasound-responsive ES-Cu-loaded microbubbles (ES-Cu MBs) to sequentially remodel the tumor microenvironment and potentiate cuproptosis immunotherapy. ECN-NO selectively colonized tumors and continuously released NO, thereby normalizing tumor vasculature, alleviating hypoxia, and facilitating the intratumoral generation, delivery, and penetration of ES-Cu nanotherapeutics following ultrasound-responsive microbubble destruction (UTMD). The enhanced intratumoral accumulation of ES-Cu amplified cuproptosis-induced oxidative stress, which triggered bacterial lysis to both establish an arginine-dependent nitroxidative amplification cascade and intrinsically limit bacterial persistence, resulting in robust peroxynitrite (ONOO⁻) generation. Consequently, ONOO⁻ disrupted glutamine metabolism, reinforced cuproptosis, and potentiated immunological activation. This temporally coordinated strategy of tumor microenvironment remodeling, cuproptosis amplification, and immune activation elicited potent systemic antitumor immunity and durable immunological memory. Together, these findings establish a self-regulating bacterial–nanomedicine strategy for enhancing cuproptosis-based cancer immunotherapy.

Triple-negative breast cancer (TNBC) is an aggressive malignancy characterized by poor prognosis, limited treatment options, and resistance to conventional therapies. Sonodynamic therapy (SDT) has emerged as a promising non-invasive approach that leverages ultrasound to activate sonosensitizers and generate cytotoxic reactive oxygen species (ROS). However, the therapeutic efficacy of SDT is frequently compromised by the overactivation of antioxidant pathways, notably the Keap1-Nrf2-ARE axis. In this study, we developed a multifunctional and ultrastable cerasome-based nanoplatform (ML385@PC-iRGD) that co-delivers a porphyrinbased sonosensitizer and the Nrf2 inhibitor ML385, with surface functionalization by the tumor-penetrating peptide iRGD. The cerasomes, stabilized by a siloxane surface network, exhibited excellent stability and prolonged circulation time. In vitro and in vivo studies demonstrated that ML385@PC-iRGD efficiently accumulated in tumors, enhanced cellular uptake via iRGD-mediated targeting, and triggered robust ROS production under ultrasound irradiation. Importantly, the co-delivery of ML385 suppressed Nrf2-driven antioxidant defenses, leading to amplified oxidative stress. This synergistic "ROS burst + defense blockade" strategy effectively overcome the intrinsic resistance of TNBC to oxidative therapies. Overall, our study highlights the potential of cerasome-based nanocarriers as a powerful and stable delivery system for combinatorial SDT and molecular inhibition, offering a promising therapeutic avenue for the treatment of refractory breast cancers.

Pancreatic cancers(PCs)is a common malignant tumor with poor prognosis in the digestive system.Its main treatment methods include surgery,radiotherapy,chemotherapy,and targeted therapy.The early diagnosis rate of hidden onset of PCs is low,and most patients have already lost the opportunity to undergo surgery when diagnosed with PCs.Chemotherapy is still the main treatment for advanced PCs,but the use of chemotherapy drugs in PCs can easily lead to drug resistance.The most significant feature that distinguishes PCs from other tumors is its rich and dense matrix,which not only hinders drug penetration but also impedes the infiltration of immune cells.The above reasons have led to a very low survival rate of PCs patients.Therefore,drug delivery systems are very important in the diagnosis and treatment of PCs.They can improve drug delivery,enhance biological barrier penetration,reduce side effects,and combine multiple treatment methods.Therefore,the treatment prospects of PCs are very broad.Currently,drug delivery systems widely applied in PCs primarily include nanodrug delivery systems,tumor microenvironment-targeted drug delivery system,immunotherapy drug delivery system,gene therapy drug delivery system,and combination therapy drug delivery system that synergize multiple therapeutic modalities.Emerging drug delivery systems(DDSs)have revolutionized PCs treatment by addressing these challenges through multiple mechanisms.Nanoformulations improve drug solubility,prolong circulation time,and reduce systemic toxicity via passive/active targeting.Smart DDSs responsive to PCs-specific stimuli enable extracellular matrix degradation,tumor-associated fibroblasts reprogramming,and vascular normalization to enhance drug accessibility.Last but not least,carrier systems loaded with myeloid-derived suppressor cell inhibitors or T cell activators can reverse immunosuppression and potentiate immunotherapy efficacy.Advanced platforms co-deliver chemotherapeutics with immunomodulators,gene-editing tools,or sonodynamic agents to achieve synergistic antitumor effects.These platforms aim to address critical challenges in PCs treatment,such as enhancing drug bioavailability,overcoming stromal barriers,reprogramming immunosuppressive niches,and achieving multi-mechanistic antitumor effects.This article provides a systematic summary and prospective analysis of the current development status,latest cutting-edge advances,opportunities,and challenges of the above-mentioned drug delivery systems in the field of PCs therapy.

Although immune checkpoint inhibitor-based immunotherapy has shown clinical efficacy in various cancer types, its efficacy in pancreatic cancer remains limited. This limitation is primarily attributed to the dense stromal tumor microenvironment (TME) and highly immunosuppressive TME of pancreatic cancer. The dense stromal TME forms a physical barrier that severely hinders the penetration and accumulation of therapeutic agents and immune cells. Additionally, it collaborates with the immunosuppressive TME to weaken immune responses against tumors. To overcome these challenges, a piezoelectric nanoparticle system, BTO@BAL, was developed, which combined piezoelectric nanomaterial barium titanate (BTO), a targeting peptide, and an amphiphilic prodrug molecule. The prodrug molecule is composed of a small-molecule PD-L1 inhibitor (BMS1166) and a nitric oxide (NO) donor (Arg)9, linked by a thioketal bond. Upon ultrasound (US)-triggered piezocatalysis, BTO continuously generated reactive oxygen species (ROS) in the hypoxic TME. On the one hand, ROS oxidized (Arg)9 to release NO, which degraded the dense stromal barrier of pancreatic cancer, remodeled the TME, improved tumor mechanical properties, and reduced stiffness. Combined with the targeted peptide, this strategy synergistically improved drug delivery efficiency. Furthermore, the combined action of ROS and NO enhanced the immunogenicity of pancreatic cancer, promoting the activation and maturation of local dendritic cells, thereby strengthening antitumor immune responses. On the other hand, ROS induced thioketal bond cleavage to release BMS1166, effectively down-regulating PD-L1 expression on KPC cells, reshaping the immunosuppressive TME of pancreatic cancer, and further amplifying the efficacy of immunotherapy. This strategy integrated US-triggered piezocatalysis with gas therapy, greatly enhancing pancreatic cancer immunotherapy and offering a theoretical foundation for developing tumor theranostic platforms.

Sonodynamic therapy (SDT) for pancreatic cancer is often constrained by inadequate tumor site-specific drug delivery and tumor microenvironment (hypoxic regions), which primarily stems from its abundant fibrotic stroma, acting as a natural physical barrier. In addition, pancreatic cancer is a cold tumor, with tumor immunosuppressive microenvironment, low amount of T cell infiltration, and large number of fibrotic and immunosuppressive cells such as regulatory T cells (Treg cells), resulting in poor therapeutic effect. Herein, we construct SPL nanoliposome (SPL NPs) consisting of DSPE-PEG2000-SNO, pyropheophorbide phospholipids (PPAL), and DSPE-PEG2000-LFC131, which operate as nitric oxide (NO) prodrug, sonosensitizer, and targeting group, respectively. With ultrasound irradiation, reactive oxygen species (ROS) were generated and triggered the release of NO, and their combination can further generate more active peroxynitrite ions (ONOO-), showing effectively tumor cell killing effect. The released NO can loosen the pancreatic cancer matrix, facilitating the penetration of nanodrugs, as well as the infiltration of immune cells. Significant immunogenic cell death (ICD) was achieved, when combined with PD-L1 immune checkpoint blockade (ICB) therapy, significantly increased anti-tumor efficacy against highly malignant KPC tumors in mice was observed, showing great potential for cancer therapy.