Decellularized Tumor Tissues Integrated with Polydopamine for Wound Healing.

Natural biomaterials have been showing extensive potential in wound healing; attempts therefore focus on productions achieving both antimicrobial and tissue regenerative abilities. Here, we construct a decellularized human colon tumor (DHCT)-derived scaffold for wound remolding via microfluidic bioprinting. The DHCT retains a series of growth factors, fibrin, and the collagen configuration, that favor tissue repair and reconstruction. Specifically, the scaffold shows superior abilities in cell migration and angiogenesis. The biocompatible scaffold is also imparted with tissue adhesion ability and photothermal effect due to the coating of biologically derived polydopamine on the surface. The strong photothermal effect under near-infrared irradiation also present the scaffold with an antibacterial rate exceeding 90%. Furthermore, in vivo experiments convinced that the polydopamine-integrated DHCT scaffold can markedly expedite the healing process of acute extensive wounds. These findings indicate that composite materials derived from natural tumors have substantial potential in pertinent clinical applications.

Bio-inspired biorthogonal compartmental microparticles for tumor chemotherapy and photothermal therapy.

Microcarrier is a promising drug delivery system demonstrating significant value in treating cancers. One of the main goals is to devise microcarriers with ingenious structures and functions to achieve better therapeutic efficacy in tumors. Here, inspired by the nucleus-cytoplasm structure of cells and the material exchange reaction between them, we develop a type of biorthogonal compartmental microparticles (BCMs) from microfluidics that can separately load and sequentially release cyclooctene-modified doxorubicin prodrug (TCO-DOX) and tetrazine-modified indocyanine green (Tz-ICG) for tumor therapy. The Tz-ICG works not only as an activator for TCO-DOX but also as a photothermal agent, allowing for the combination of bioorthogonal chemotherapy and photothermal therapy (PTT). Besides, the modification of DOX with cyclooctene significantly decreases the systemic toxicity of DOX. As a result, the developed BCMs demonstrate efficient in vitro tumor cell eradication and exhibit notable tumor growth inhibition with favorable safety. These findings illustrate that the formulated BCMs establish a platform for bioorthogonal prodrug activation and localized delivery, holding significant potential for cancer therapy and related applications.

Engineering of a DNA/γPNA Hybrid Nanoreporter for ctDNA Mutation Detection via γPNA Urinalysis.

Detection of circulating tumor DNA (ctDNA) mutations, which are molecular biomarkers present in bodily fluids of cancer patients, can be applied for tumor diagnosis and prognosis monitoring. However, current profiling of ctDNA mutations relies primarily on polymerase chain reaction (PCR) and DNA sequencing and these techniques require preanalytical processing of blood samples, which are time-consuming, expensive, and tedious procedures that increase the risk of sample contamination. To overcome these limitations, here the engineering of a DNA/γPNA (gamma peptide nucleic acid) hybrid nanoreporter is disclosed for ctDNA biosensing via in situ profiling and recording of tumor-specific DNA mutations. The low tolerance of γPNA to single mismatch in base pairing with DNA allows highly selective recognition and recording of ctDNA mutations in peripheral blood. Owing to their remarkable biostability, the detached γPNA strands triggered by mutant ctDNA will be enriched in kidneys and cleared into urine for urinalysis. It is demonstrated that the nanoreporter has high specificity for ctDNA mutation in peripheral blood, and urinalysis of cleared γPNA can provide valuable information for tumor progression and prognosis evaluation. This work demonstrates the potential of the nanoreporter for urinary monitoring of tumor and patient prognosis through in situ biosensing of ctDNA mutations.

A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation.

Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.

Hierarchical mesoporous silicon and albumin composite microparticles delivering DOX and FU for liver cancer treatment.

Drug delivery systems based on hydrogel microcarriers have shown enormous achievements in tumor treatment. Current research direction mainly concentrated on the improvement of the structure and function of the microcarriers to effectively deliver drugs for enhanced cancer treatment with decreased general toxicity. Herein, we put forward novel hierarchical mesoporous silicon nanoparticles (MSNs) and bovine serum albumin (BSA) composite microparticles (MPMSNs@DOX/FU) delivering doxorubicin (DOX) and 5-fluorouracil (FU) for effective tumor therapy with good safety. The DOX and FU could be efficiently loaded in the MSNs, which were further encapsulated into methacrylate BSA (BSAMA) microparticles by applying a microfluidic technique. When transported to the tumor area, DOX and FU will be persistently released from the MPMSNs@DOX/FU and kept locally to lessen general toxicity. Based on these advantages, MPMSNs@DOX/FU could observably kill liver cancer cells in vitro, and evidently suppress the tumor development of liver cancer nude mice model in vivo. These results suggest that such hierarchical hydrogel microparticles are perfect candidates for liver cancer treatment, holding promising expectations for impactful cancer therapy.

Programming peptide-oligonucleotide nano-assembly for engineering of neoantigen vaccine with potent immunogenicity.

Background: Neoantigen nanovaccine has been recognized as a promising treatment modality for personalized cancer immunotherapy. However, most current nanovaccines are carrier-dependent and the manufacturing process is complicated, resulting in potential safety concerns and suboptimal codelivery of neoantigens and adjuvants to antigen-presenting cells (APCs). Methods: Here we report a facile and general methodology for nanoassembly of peptide and oligonucleotide by programming neoantigen peptide with a short cationic module at N-terminus to prepare nanovaccine. The programmed peptide can co-assemble with CpG oligonucleotide (TLR9 agonist) into monodispersed nanostructures without the introduction of artificial carrier. Results: We demonstrate that the engineered nanovaccine promoted the codelivery of neoantigen peptides and adjuvants to lymph node-residing APCs and instigated potent neoantigen-specific T-cell responses, eliciting neoantigen-specific antitumor immune responses with negligible systemic toxicity. Furthermore, the antitumor T-cell immunity is profoundly potentiated when combined with anti-PD-1 therapy, leading to significant inhibition or even complete regression of established melanoma and MC-38 colon tumors. Conclusions: Collectively, this work demonstrates the feasibility and effectiveness of personalized cancer nanovaccine preparation with high immunogenicity and good biosafety by programming neoantigen peptide for nanoassembly with oligonucleotides without the aid of artificial carrier.

Pyroptosis-related gene signature for predicting gastric cancer prognosis.

Gastric cancer (GC) is a prevalent form of malignancy characterized by significant heterogeneity. The development of a specific prediction model is of utmost importance to improve therapy alternatives. The presence of H. pylori can elicit pyroptosis, a notable carcinogenic process. Furthermore, the administration of chemotherapeutic drugs is often employed as a therapeutic approach to addressing this condition. In the present investigation, it was observed that there were variations in the production of 17 pyroptosis-regulating proteins between stomach tissue with tumor development and GC cells. The predictive relevance of each gene associated with pyroptosis was assessed using the cohort from the cancer genome atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) was utilized to enhance the outcomes of the regression approach. Patients with gastric cancer GC in the cohort from the TCGA were categorized into low-risk or high-risk groups based on their gene expression profiles. Patients with a low risk of gastric cancer had a higher likelihood of survival compared to persons classified as high risk (P<0.0001). A subset of patients diagnosed with GC from a Genes Expression Omnibus (GEO) cohort was stratified according to their overall survival (OS) duration. The statistical analysis revealed a higher significance level (P=0.0063) regarding OS time among low-risk individuals. The study revealed that the GC risk score emerged as a significant independent prognostic factor for OS in patients diagnosed with GC. The results of Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) research revealed that genes associated with a high-risk group had significantly elevated levels of immune system-related activity. Furthermore, it was found that the state of immunity was diminished within this particular group. The relationship between the immune response to cancer and pyroptosis genes is highly interconnected, suggesting that these genes have the potential to serve as prognostic indicators for GC.

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy.

The induction of cuproptosis, a recently identified form of copper-dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu2+) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis-inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis-mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor-infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death-1 (PD-1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis-mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.

Curcumin-encapsulated fish gelatin-based microparticles from microfluidic electrospray for postoperative gastric cancer treatment.

Gastric cancer is the fifth most frequently diagnosed malignant neoplasm and the third leading cause of cancer-related mortality. Nevertheless, the therapeutic efficacy of conventional surgical and chemotherapeutic interventions in clinical practice is often unsatisfactory. Curcumin (Cur) has shown promise as a therapeutic agent in prior studies. However, its progress in this context has been impeded by challenges including low solubility, instability in aqueous environments, and rapid metabolism. In this study, we develop methacrylate fish gelatin (FGMA) hydrogel microparticles (FGMPs@Cur) encapsulating Cur via microfluidic electrospray technology for postoperative comprehensive treatment of gastric cancer. Comprehensive characterizations and analyses were conducted to assess the cytotoxicity against gastric cancer cells and potential tissue reparative effects of FGMPs@Cur. In vitro experiments revealed that FGMPs@Cur exhibited a remarkable cytotoxic effect on nearly 80 % of gastric cancer cells while maintaining at least 95 % viability of normal cells in cell compatibility tests. In vivo results demonstrated that FGMPs@Cur significantly reduced tumor volume to 47 % of the control group, and notable tissue regeneration was observed at the surgical site. These properties indicated that such a hydrogel microparticle system is a promising candidate for postoperative gastric cancer treatment in practical application.

Engineering Heterogeneous Tumor Models for Biomedical Applications.

Tumor tissue engineering holds great promise for replicating the physiological and behavioral characteristics of tumors in vitro. Advances in this field have led to new opportunities for studying the tumor microenvironment and exploring potential anti-cancer therapeutics. However, the main obstacle to the widespread adoption of tumor models is the poor understanding and insufficient reconstruction of tumor heterogeneity. In this review, the current progress of engineering heterogeneous tumor models is discussed. First, the major components of tumor heterogeneity are summarized, which encompasses various signaling pathways, cell proliferations, and spatial configurations. Then, contemporary approaches are elucidated in tumor engineering that are guided by fundamental principles of tumor biology, and the potential of a bottom-up approach in tumor engineering is highlighted. Additionally, the characterization approaches and biomedical applications of tumor models are discussed, emphasizing the significant role of engineered tumor models in scientific research and clinical trials. Lastly, the challenges of heterogeneous tumor models in promoting oncology research and tumor therapy are described and key directions for future research are provided.

Proteome-wide analysis reveals potential therapeutic targets for Colorectal cancer: a two-sample mendelian randomization study.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, highlighting an unmet clinical need for more effective therapies. This study aims to evaluate the causal relationship between 4,489 plasma proteins and CRC to identify potential therapeutic targets for CRC. METHODS: We conducted two-sample Mendelian randomization (MR) analysis to examine the causal effects of plasma proteins on CRC. Mediation analysis was performed to assess the indirect effects of plasma proteins on CRC through associated risk factors. In addition, we conducted a phenome-wide association study using the UK Biobank dataset to examine associations between these plasma proteins and other phenotypes. RESULTS: Out of 4,489 plasma proteins, MR analysis revealed causal associations with CRC for 23 proteins, including VIMP, MICB, TNFRSF11B, C5orf38 and SLC5A8. Our findings also confirm the associations between reported risk factors and CRC. Mediation analysis identified mediating effects of proteins on CRC outcomes through risk factors. Furthermore, MR analysis identified 154 plasma proteins are causally linked to at least one CRC risk factor. CONCLUSIONS: Our study evaluated the causal relationships between plasma proteins and CRC, providing a more complete understanding of potential therapeutic targets for CRC.

Designing Bioorthogonal Reactions for Biomedical Applications.

Bioorthogonal reactions are a class of chemical reactions that can be carried out in living organisms without interfering with other reactions, possessing high yield, high selectivity, and high efficiency. Since the first proposal of the conception by Professor Carolyn Bertozzi in 2003, bioorthogonal chemistry has attracted great attention and has been quickly developed. As an important chemical biology tool, bioorthogonal reactions have been applied broadly in biomedicine, including bio-labeling, nucleic acid functionalization, drug discovery, drug activation, synthesis of antibody-drug conjugates, and proteolysis-targeting chimeras. Given this, we summarized the basic knowledge, development history, research status, and prospects of bioorthogonal reactions and their biomedical applications. The main purpose of this paper is to furnish an overview of the intriguing bioorthogonal reactions in a variety of biomedical applications and to provide guidance for the design of novel reactions to enrich bioorthogonal chemistry toolkits.

An autocatalytic multicomponent DNAzyme nanomachine for tumor-specific photothermal therapy sensitization in pancreatic cancer.

Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic gene regulation has rarely been studied. Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core to load the photothermal therapy (PTT) dye IR780 and the calcium efflux pump inhibitor curcumin. Then, the MNAzyme is distributed into the hydrophilic PEG layer and sealed with calcium phosphate through biomineralization. Moreover, RGD is attached to the outer tail of PEG for tumor targeting. The constructed nanomachine can release MNAzyme and the cofactor Ca2+ under acidic conditions and self-assemble into an active mode to cleave heat shock protein (HSP) mRNA by consuming the oncogene miRNA-21. Silencing miRNA-21 enhances the expression of the tumor suppressor gene PTEN, leading to PTT sensitization. Meanwhile, curcumin maintains high intracellular Ca2+ to further suppress HSP-chaperone ATP by disrupting mitochondrial Ca2+ homeostasis. Therefore, pancreatic cancer is triple-sensitized to IR780-mediated PTT. The in vitro and in vivo results show that the MNAzyme-based nanomachine can strongly regulate HSP and PTEN expression and lead to significant pancreatic tumor inhibition under laser irradiation.

Study on secondary metabolites of endophytic fungus Diaporthe sp. AC1 induced by tryptophan analogs.

Small molecule-induced fermentation of the endophytic fungus Diaporthe sp. AC1 originated from Artemisia argyi was executed to investigate its secondary metabolites. It was fermented in a culture medium containing 5-hydroxytryptophan (5-HTP), 1-methyl-L-tryptophan (1-MT), and tryptamine (TA), respectively. The antibacterial activities of crude extracts against pathogenic bacteria and pathogenic fungi were determined by using the Oxford cup method, while the cytotoxicity of crude extracts against cancer cells was determined by using the MTT method. The results showed that the secondary metabolites of Diaporthe sp. AC1 induced by 1-MT exhibited optimal antibacterial activity and tumor cytotoxicity. The induction conditions of 1-MT were optimized, and the antibacterial activities and tumor cytotoxicity of crude extracts under different induction conditions were investigated. As indicated, the optimal moment for 1-MT addition was before inoculation and its optimal concentration was 0.25 mM. Under these conditions, Diaporthe sp. AC1 was fermented and approximately 12 g of crude extracts was obtained. The crude extracts were then separated and purified to acquire nine monomer compounds, including three new compounds (1-3) and six known compounds (4-9). The antibacterial activities of the compounds against pathogenic bacteria and pathogenic fungi were investigated by using the microdilution method, while their cytotoxicity against cancer cells was analyzed by using the MTT method. The results demonstrated that Compound 1 exhibited moderate antibacterial activities against Verticillium dahlia, Fusarium graminearum, and Botrytis cinerea, as well as a low inhibitory activity against Listeria monocytogenes. Nevertheless, Compound 1 showed significant cytotoxicity against five cancer cells, with IC50 ranging from 12.26 to 52.52 µM. Compounds 2 and 3 exhibited negligible biological activity, while other compounds showed detectable inhibitory activities against pathogenic bacteria and cancer cells.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy.

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

Screening of novel serum biomarkers for gastric cancer in coastal populations using a protein microarray.

Gastric cancer (GC) has high rates of morbidity and mortality, and this phenomenon is particularly evident in coastal regions where local dietary habits favor the consumption of pickled foods such as salted fish and vegetables. In addition, the diagnosis rate of GC remains low due to the lack of diagnostic serum biomarkers. Therefore, in this study, we aimed to identify potential serum GC biomarkers for use in clinical practice. To identify candidate biomarkers of GC, 88 serum samples were first screened using a high-throughput protein microarray to measure the levels of 640 proteins. Then, 333 samples were used to validate the potential biomarkers using a custom antibody chip. ELISA, western blot, and immunohistochemistry were then used to verify the expression of the target proteins. Finally, logistic regression was performed to select serum proteins for the diagnostic model. As a result, five specific differentially expressed proteins, TGFß RIII, LAG-3, carboxypeptidase A2, Decorin and ANGPTL3, were found to have the ability to distinguish GC. Logistic regression analysis showed that the combination of carboxypeptidase A2 and TGFß RIII had superior potential for diagnosing GC (area under the ROC curve [AUC] = 0.801). The results suggested that these five proteins alone and the combination of carboxypeptidase A2 and TGFß RIII may be used as serum markers for the diagnosis of GC.

Antimicrobial and Cytotoxic Activity of Endophytic Fungi from Lagopsis supina.

In this study, five endophytic fungi belonging to the Aspergillus and Alternaria genera were isolated from Lagopsis supina. The antimicrobial activity of all fungal fermented extracts against Staphylococcus and Fusarium graminearum was tested using the cup-plate method. Among them, Aspergillus ochraceus XZC-1 showed the best activity and was subsequently selected for large-scale fermentation and bioactivity-directed separation of the secondary metabolites. Four compounds, including 2-methoxy-6-methyl-1,4-benzoquinone (1), 3,5-dihydroxytoluene (2), oleic acid (3), and penicillic acid (4) were discovered. Here, compounds 1 and 4 displayed anti-fungal activity against F. graminearum, F. oxysporum, F. moniliforme, F. stratum, Botrytis cinerea, Magnaporthe oryzae, and Verticillium dahliae with diverse MIC values (128-512 µg/ml), which were close to that of the positive control antifungal, actidione (64-128 µg/ml). Additionally, compounds 1 and 4 also exhibited moderate antibacterial activity against S. aureus, Listeria monocytogenes, Escherichia coli, and Salmonella enterica, with low MIC values (8-64 µg/ml). Moreover, compounds 1 and 4 displayed selective cytotoxicity against cancer cell lines as compared with the normal fibroblast cells. Therefore, this study proposes that the endophytic fungi from L. supina can potentially produce bioactive molecules to be used as lead compounds in drugs or agricultural antibiotics.

Near-infrared light-responsive Nitric oxide microcarrier for multimodal tumor therapy.

Nitric oxide (NO) has shown great potential in tumor therapy, and the development of a platform for precise and controllable NO release still needs to be explored. Herein, a microfluidic electrospray strategy is proposed for the fabrication of hydrogel microspheres encapsulating NO donors (S-nitrosoglutathione, GSNO) together with black phosphorus (BP) and chemotherapeutic doxorubicin (DOX) as microcarriers for tumor therapy. Based on the excellent photothermal property of BP and thermal sensitivity of GSNO, the microcarriers exhibit a near-infrared light (NIR)-responsive NO release behavior. Besides, the photothermal performance of the microcarriers accelerates the release of DOX. All these contribute to the excellent tumor-killing effect of the microcarriers by combining multiple therapeutic strategies including NO therapy, photothermal therapy, and chemotherapy. Moreover, it was demonstrated that the NIR-responsive NO delivery microcarriers could significantly inhibit tumor growth without apparent side effects in vivo. Therefore, it is believed that the novel NIR-responsive NO microcarriers are promising candidates in clinical tumor therapy applications.

Noninvasive Multiplexed Analysis of Bladder Cancer-Derived Urine Exosomes via Janus Magnetic Microspheres.

Bladder cancer greatly endangers human health, and its early diagnosis is of vital importance. Exosomes, which contain proteins and nucleic acids related to their source cells, are expected to be an emerging biomarker for bladder cancer detection. Here, we propose a novel system for multiplexed analysis of bladder cancer-derived urine exosomes based on Janus magnetic microspheres as barcoded microcarriers. The microcarriers are constructed by droplet-templated coassembly of colloidal silica nanoparticles and magnetic nanoparticles under a magnetic field. The microcarriers possess one hemisphere with structural color and the other hemisphere with magneto-responsiveness. Benefiting from the unique structure, these Janus microcarriers could serve as barcodes and could move controllably in a sample solution, thus realizing the multiplex detection of exosomes with high sensitivity. Notably, the present platform is noninvasive since a urine specimen, as an ideal source of bladder cancer-derived exosomes, is employed as the sample solution. This feature, together with the good sensitivity, specificity, low sample consumption, and easy operation, indicates the great potential of the platform for bladder cancer diagnosis in clinical applications.

Hierarchical Microparticles Delivering Oxaliplatin and NLG919 Nanoprodrugs for Local Chemo-immunotherapy.

Chemo-immunotherapy shows promising antitumor therapeutic outcomes for many primary cancers. Research in this area has been focusing on developing an ideal formula that enables the potent efficacy of chemo-immunotherapy in combating various cancers with reduced systemic toxicity. Herein, we present novel hierarchical hydrogel microparticles (MDDP) delivering oxaliplatin and NLG919 nanoprodrugs for local chemo-immunotherapy with desired features. The oxaliplatin prodrug and NLG919 were efficiently loaded in the dual-drug polymeric nanoparticles (DDP NPs), which were further encapsulated into a MDDP by using microfluidic technology. When delivered to the tumor site, the DDP NPs will be sustainedly released from the MDDP and retained locally to reduce systemic toxicity. After being endocytosed by cancer cells, the cytotoxic oxaliplatin and NLG919 could be successfully triggered to release from DDP NPs in a chain-shattering manner, leading to the immunogenic cell death (ICD) of tumor cells and the suppression of intratumoral immunosuppressive Tregs, respectively. With the assistance of an immune modulator, the chemotherapeutics-induced ICD could trigger robust systemic antitumor immune responses, presenting superior synergistic antitumor efficacies. Thus, the hierarchical microparticles could substantially inhibit the growth of mouse subcutaneous colorectal tumors, breast tumors, and colorectal tumors with large initial sizes via synergized chemo-immunotherapy, showing great potential in the practical clinical application of oncotherapy.