To evaluate the long-term outcomes of half-dose half-dose photodynamic therapy (PDT) in the treatment of bullous variant central serous chorioretinopathy (bvCSC). A retrospective single-center study of 18 patients, 31 eyes with bvCSC who received PDT between January 2012 and December 2021 with a minimum follow-up of 36 months. During follow-up, a dry macula was achieved in all cases and no recurrence was witnessed. The mean number of PDT treatments was 1.2 sessions. Twenty-five (80.6

Supplementary Table S1: Antibody list.

Under the nutrient-deprived tumor microenvironment (TME) and near-universal KRAS mutations, pancreatic ductal adenocarcinoma (PDAC) exhibits voracious addiction to glutamine metabolism. This aberrant metabolism not only sustains the rapid proliferation of malignant cells, but also shapes a tumor-permissive TME characterized by stromal desmoplasia and immunosuppression, culminating in the clinical refractoriness of PDAC. Although multi-target synergistic modulation of glutamine metabolism is recognized as a requisite antitumor strategy, its implementation is still hampered by the uncontrolled in vivo multi-drug biodistribution. Therefore, glutamine metabolism modulation is in urgent need of precision codelivery of multiple drugs. Herein, we propose an upstream-downstream synergistic glutamine metabolism modulation strategy and develop a size switchable metabolic nanomodulators (J&V@T-PPLN NPs) for precision codelivery of metabolic modulators. This nanomodulator achieves in vivo ratio-precise dual-drug codelivery, synergistically blocking the uptake and utilization of glutamine by PDAC cells. Beyond cutting off nutrient supply to malignant cells, the nanomodulator also demonstrates the capacity to remodel the TME and reactivate antitumor immunity, thereby eliciting enhanced tumor suppression. Through the ratio-precise codelivery system, this study discussed the possibility of translating in vitro validated synergistic metabolism modulation into a controllable in vivo combination therapy modality, providing a generalizable strategy for metabolism modulating cancer therapy and the rational design of precision drug delivery systems.

The synergistic integration of chemotherapy and immunotherapy represents the most promising strategy for enhancing therapeutic efficacy in cancer treatment. Chemotherapy initiates the therapeutic cascade by inducing immunogenic cell death (ICD), thereby releasing tumor antigens and prime immune sensitization. Subsequently, immunotherapy blocks immune evasion pathways, resulting in a coordinated relay-like antitumor response. This temporally coordinated sequence maximizes synergistic therapeutic efficacy. However, current clinical practice cannot support the sequential and sustained administration of chemotherapy and immunotherapy. This study innovatively integrates artificial intelligence (AI) with 3D printing technology to develop a dual-layer drug-loaded implant (LEH@OG) to achieve precise spatiotemporally controlled sequential drug release. The AI model precisely predicted exposure time of the inner gel layer in advance by optimizing parameters such as outer shell thickness and concentration, thereby realizing an on-demand sequential release process. This study demonstrates that combining AI with 3D printing enables precise sequential delivery of chemotherapy-immunotherapy agents, providing a core solution for establishing personalized colorectal cancer peritoneal metastasis (CCPM) therapeutic platforms, while also offering a new paradigm for synergistic treatment of other solid tumors.

Triple-negative breast cancer (TNBC) is characterized by its unfavorable prognosis and heightened propensity for metastasis. Despite paclitaxel (PTX) chemotherapy being a cornerstone of treatment, it can paradoxically promote metastasis by facilitating Padi4-mediated nuclear expulsion and triggering the RAGE/ERK pathway. In this investigation, we engineered a tumor-responsive nanoparticle platform (RAPG) capable of codelivering PTX, the Padi4 inhibitor GSK484, and a RAGE antagonist peptide (RAP). The RAPG nanoparticles exhibited redox-sensitive drug release, precise tumor localization, and deep tissue permeation. Mechanistically, RAPG suppressed histone citrullination, impeded RAGE/ERK signaling, and reinforced conventional apoptotic pathways. In both in vitro and in vivo assessments, RAPG attenuated epithelial-mesenchymal transition markers and reduced tumor invasiveness, circulating tumor cells, and lung metastasis, while enhancing treatment efficacy and prolonging survival. This study presents a promising strategy to counteract chemotherapy-induced metastasis in TNBC through concurrent inhibition of Padi4-mediated histone citrullination and RAGE/ERK signaling.

Supplementary Fig. S3: ScRNAseq analysis of ICC TME after GC-based therapies in orthotopic murine 425-ICC model.

Glioblastoma (GBM) remains incurable and exhibits exceptionally high metabolic demands, driving the evolution of hyperactive mitochondrial systems within tumors. In parallel, mitochondrial transfer from astrocytes to cancer cells fuels metabolic reprogramming and enhances GBM tumorigenicity. These malignant traits markedly constrain therapeutic efficacy and patient survival. Herein, we report a dehydroascorbic acid (DHA)-functionalized, ROS-responsive, ferrocene-integrated polymer nanoplatform (GS@DFP) co-loaded with S-Gboxin and Galunisertib, simultaneously targeting GBM mitochondria and mitochondrial transfer in astrocyte-cancer cell crosstalk. After crossing the blood-brain barrier (BBB) through Glut1-mediated transport enabled by DHA, GS@DFP responds to elevated intracellular reactive oxygen species (ROS) levels in GBM to trigger payload release and initiate Fenton reactions. S-Gboxin inhibits mitochondrial complex V and depletes ATP, whereas Galunisertib downregulates TGF-β/SMAD-driven thrombospondin-1 (TSP-1) expression, suppressing tumor microtube (MT) formation and thereby reducing astrocyte-to-GBM mitochondrial transfer. Notably, TGF-β inhibition also reprograms the immunosuppressive tumor microenvironment (TME). This work establishes a multifunctional nanoplatform that targets mitochondrial vulnerabilities and intercellular crosstalk, offering a translatable strategy for enhancing GBM therapy. Mitochondrial transfer from astrocytes to cancer cells fuels metabolic reprogramming and enhances glioblastoma (GBM) tumorigenicity. Here this group reports a polymeric nanoplatform co-loading S-Gboxin and Galunisertib targeting GBM mitochondria and mitochondrial transfer in astrocyte-cancer cell crosstalk, thereby enhancing GBM therapeutic efficacy.

Quantum dots (QDs) have emerged as versatile nanomaterials with significant potential for cancer therapy due to their unique optical properties, biocompatibility and multifunctionality. Through surface modification, QDs can target tumor-specific biomarkers, serving both as direct therapeutic agents and precision drug delivery vehicles. Their ability to generate reactive oxygen species (ROS) under near-infrared light excitation enables the integration of photothermal and photodynamic therapies, enhancing antitumor efficacy. Additionally, QDs possess intrinsic antimicrobial properties that inhibit bacterial growth within the tumor microenvironment, reducing infection-related complications and improving therapeutic outcomes. Despite these advantages, challenges such as heavy metal toxicity and uncontrolled degradation remain, necessitating the development of non-toxic, heavy metal-free QDs and advanced surface engineering. This review discusses the molecular design, antitumor mechanisms, and clinical translation challenges of QD-based platforms, highlighting their emerging role in precision oncology and suggesting future directions in the development of smart, multifunctional systems that integrate multiple therapeutic modalities for enhanced cancer treatment.

Glioblastoma (GBM), constrained by the limited cranial space and the blood-brain barrier (BBB), establishes a rapidly adaptable, generalized communication network through enhanced terminal sialylation of membrane proteins. This metabolism-driven network encodes cellular metabolic states into functional information at the membrane level, thereby markedly enhancing signaling plasticity, intercellular communication, and immune evasion, which together sustain and expand malignant phenotypes within a resource-limited microenvironment. Here, a "metabolism-guided decoding of communication architecture" strategy is proposed and developed a brain-targeted pathogen-derived nano-interferer (OMV@HM-T/F). By simultaneously inhibiting glycosylation precursor synthesis and sialic acid activation, the platform remodels membrane glycan structures, disrupts glycan-dependent communication scaffolds, and effectively blocks downstream signal amplification and immune suppression pathways. Integrating BBB penetrability with tumor microenvironment responsiveness, this strategy enables precise metabolic-level intervention, offering a promising approach to overcoming high adaptability and therapeutic resistance.

Retinal pigment epithelium (RPE) degeneration is the pathological hallmark of multifactorial dry age-related macular degeneration (dAMD). Mounting evidence implicates oxidative stress and aberrant activation of mammalian target of rapamycin (mTOR) as key drivers of this process. Recent studies have shown that simultaneous modulation of these pathways may offer therapeutic benefit. However, clinical trials of rapamycin, an mTOR inhibitor widely employed in retinal research, have demonstrated limited efficacy, potentially due to poor bioavailability and paradoxical effects on RPE and photoreceptors. To overcome these challenges, APMNP@Rapa, a rapamycin-loaded, methionine-based ROS-responsive polymeric micellar system functionalized with an Ab peptide for active targeting of damaged RPE is developed. The micelles self-assemble from poly(ethylene glycol) - poly-methionine copolymers, leveraging methionine's endogenous nature and innate biocompatibility as an innovative ROS-responsive motif. This design yields particles with exceptional circulation stability and enhanced biocompatibility. In the high-ROS microenvironment of diseased RPE, APMNP@Rapa triggers on-demand rapamycin release. In a sodium iodate (NaIO 3 )-induced RPE oxidative stress model, APMNP@Rapa simultaneously inhibited aberrant mTOR activation, attenuated oxidative damage, and suppressed inflammatory response. These combined effects resulted in a marked preservation of the retina against degradation. Overall, the research establishes a paradigm for intravenous treatment of dAMD using multifunctional nanotherapy.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis. Conventional chemo-radiotherapy demonstrates limited therapeutic efficacy and is often accompanied by significant side effects, largely due to factors such as drug resistance, radiation resistance, the presence of the blood-brain barrier (BBB), and the activation of DNA damage repair mechanisms. There is a pressing need to enhance treatment efficacy, with BRD4 identified as a promising target for increasing GBM sensitivity to therapy. Lacking small molecule inhibitors, BRD4 can be degraded using PROteolysis Targeting Chimera (PROTAC), thereby inhibiting DNA damage repair. To deliver PROTAC, SIAIS171142 (SIS) effectively, we designed a responsive nanocapsule, MPL(SS)P@SIS, featuring GBM-targeting and GSH-responsive drug release. Modified with 1-methyl-l-tryptophan (MLT), nanocapsules facilitate targeted delivery of SIS, downregulating BRD4 and sensitizing GBM cells to radiotherapy and chemotherapy. After intravenous administration, MPL(SS)P@SIS selectively accumulates in tumor tissue, enhancing the effects of radiotherapy and temozolomide (TMZ) by increasing DNA damage and oxidative stress. GSH activates the nanocapsules, triggering BRD4 degradation and hindering DNA repair. In mouse models, the nanosensitizer, combined with TMZ and X-ray irradiation, efficiently inhibited the growth of GBM. These findings demonstrate a novel PROTAC-based sensitization strategy targeting BRD4, offering a promising approach for effective GBM therapy.

Liver fibrosis (LF) is characterized by excessive production of reactive oxygen species (ROS), abnormal activation of hepatic stellate cells (HSCs), and subsequent extracellular matrix (ECM) deposition. The complexity of multiple interrelated pathways involved in this process makes it challenging for monotherapy to achieve the desired therapeutic effects. To address this issue, this study designs a ROS-activated heterodimer conjugate (VTO) to collaboratively alleviate LF. Additionally, a biomimetic high-density lipoprotein is utilized for encapsulation, resulting in the formation of PL-VTO, which enables natural liver targeting. Once PL-VTO is delivered to the fibrotic liver, it can respond and release both parent drugs upon encountering the high ROS microenvironment, effectively scavenge ROS, induce quiescence of activated HSCs, and reduce collagen deposition, ultimately reversing LF. Overall, this study presents a feasible and versatile nanotherapeutic approach to enhance the prodrug-driven treatment of LF.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge to the efficacy of gemcitabine-based chemotherapy. Aberrant activation of intracellular pyrimidine metabolism is a key factor contributing to the reduced effectiveness of gemcitabine. Combining gemcitabine with metabolic regulators targeting critical pathways may alleviate gemcitabine resistance. In this study, we focus on the abnormal activation of dihydroorotate dehydrogenase (DHODH) in PDAC cells, a pivotal enzyme in the de novo pyrimidine synthesis pathway that diminishes cellular sensitivity to gemcitabine and catalyzes the reduction of ubiquinone to ubiquinol, playing an essential role in maintaining cellular redox homeostasis. To address these challenges, we developed GE11 peptide-modified polyphenol-iron chelate nanoparticles for co-delivery the long carbon chain-modified gemcitabine and the DHODH inhibitor leflunomide, with peptide modification enabling nanoparticles to target PDAC cells with high expression of epidermal growth factor receptor. The nanoparticles demonstrated the ability to induce mitocytosis and achieve deep tumor penetration in PDAC tissues. Upon drug release at the core lesion, the three components, modified gemcitabine, leflunomide and iron ions synergistically enhanced tumor cell killing by alleviating gemcitabine resistance and disrupting cellular redox homeostasis to induce multimodal cell death. In an in situ pancreatic cancer mouse model, this strategy exhibited superior anti-tumor efficacy compared to the standard AG chemotherapy regimen (nab-paclitaxel and gemcitabine), even at a 6.3-fold lower gemcitabine concentration. These findings underscore the potential of this approach as a highly effective therapeutic strategy for PDAC treatment.

Aberrantly elevated lactate flux in tumors is increasingly recognized as a key driver of metabolic symbiosis, immunosuppression, and, ultimately, immunogenic chemotherapy resistance. Here, we propose a precise lactate homeostasis modulation strategy that selectively intercepts intracellular lactate molecules in highly glycolytic tumor cells. Targeting monocarboxylate transporter 4 (MCT4), a key lactate efflux transporter overexpressed in tumor cells, we developed a glucose-disguised delivery system for precise transport of regulatory molecules into glycolysis-dependent tumor cells. By modulating lactate-mediated crosstalk between heterogeneous tumor subpopulations (glycolysis-dependent and lactate-consuming cells) and immune cells, this strategy effectively disrupts lactate-driven metabolic cooperation within the tumor niche, which may contribute to overcoming lactate-associated resistance to chemo-immunotherapy.

Background:Bone marrow mononuclear cells (BMMNCs) therapy should be effective for the improvement of liver function and short-term outcome in patients with liver cirrhosis, but few studies have explored the long-term prognosis of cirrhotic patients treated with BMMNCs. Methods:In this retrospective study, eligible patients with liver cirrhosis were selected by using propensity score matching (PSM). Effect of BMMNCs on death was explored by Cox regression analysis, as well as competing risk analysis, where liver transplantation was a competing event. Hazard ratio (HR) and sub-distribution HR (sHR) were calculated. Subgroup analyses were performed based on the age, sex, Child-Pugh class, and model for end-stage liver disease (MELD) score. Results:Overall, 260 patients were included, of whom 130 were treated with transhepatic arterial transplantation of BMMNCs. The median follow-up duration was 5.27 (range: 0.37-16.62) years. By adjusting by age, sex, and Child-Pugh score, multivariate Cox regression (HR = 0.707, P = 0.020) and competing risk analyses (sHR = 0.709, P = 0.026) demonstrated that BMMNCs were independently associated with a lower risk of death in cirrhotic patients in the overall analysis. Univariate Cox regression analyses demonstrated that BMMNCs were significantly associated with a decreased risk of death in the subgroup analyses of age ≤50 years (HR= 0.533, P = 0.016), male (HR = 0.626, P = 0.010), Child-Pugh class B (HR = 0.638, P = 0.026), and MELD score > 12 (HR = 0.483, P = 0.002), but not age > 50 years (P = 0.097), female (P = 0.170), Child-Pugh class A (P = 0.309), Child-Pugh class C (P = 0.369), or MELD score ≤12 (P = 0.096). Conclusion:BMMNCs can provide additional survival benefits in patients with liver cirrhosis.