A method for predicting drugs that can boost the efficacy of immune checkpoint blockade.

Combination therapy is a promising therapeutic strategy to enhance the efficacy of immune checkpoint blockade (ICB); however, predicting drugs for effective combination is challenging. Here we developed a general data-driven method called CM-Drug for screening compounds that can boost ICB treatment efficacy based on core and minor gene sets identified between responsive and nonresponsive samples in ICB therapy. The CM-Drug method was validated using melanoma and lung cancer mouse models, with combined therapeutic efficacy demonstrated in eight of nine predicted compounds. Among these compounds, taltirelin had the strongest synergistic effect. Mechanistic analysis and experimental verification demonstrated that taltirelin can stimulate CD8+ T cells and is mediated by the induction of thyroid-stimulating hormone. This study provides an effective and general method for predicting and evaluating drugs for combination therapy and identifies candidate compounds for future ICB combination therapy.

Tumor-repopulating cell-derived microparticles elicit cascade amplification of chemotherapy-induced antitumor immunity to boost anti-PD-1 therapy.

Immune checkpoint blockade (ICB) therapy, particularly antibodies targeting the programmed death receptor 1 (PD-1) and its ligand (PD-L1), has revolutionized cancer treatment. However, its efficacy as a standalone therapy remains limited. Although ICB therapy in combination with chemotherapy shows promising therapeutic responses, the challenge lies in amplifying chemotherapy-induced antitumor immunity effectively. This relies on efficient drug delivery to tumor cells and robust antigen presentation by dendritic cells (DCs). Here, we developed tumor-repopulating cell (TRC)-derived microparticles with exceptional tumor targeting to deliver doxorubicin (DOX@3D-MPs) for improve anti-PD-1 therapy. DOX@3D-MPs effectively elicit immunogenic tumor cell death to release sufficient tumor antigens. Heat shock protein 70 (HSP70) overexpressed in DOX@3D-MPs contributes to capturing tumor antigens, promoting their phagocytosis by DCs, and facilitating DCs maturation, leading to the activation of CD8+ T cells. DOX@3D-MPs significantly enhance the curative response of anti-PD-1 treatment in large subcutaneous H22 hepatoma, orthotopic 4T1 breast tumor and Panc02 pancreatic tumor models. These results demonstrate that DOX@3D-MPs hold promise as agents to improve the response rate to ICB therapy and generate long-lasting immune memory to prevent tumor relapse.

Cell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy.

The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8+ T cells, especially stem-like CD8+ T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPsAFP) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPsAFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPsAFP-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8+ T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8+ T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8+ T cell proliferation and differentiation to terminally exhausted CD8+ T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.

Hydrophobicity-Adaptive Polymers Trigger Fission of Tumor-Cell-Derived Microparticles for Enhanced Anticancer Drug Delivery.

Tumor-cell-derived microparticles (MPs) can function as anticancer drug-delivery carriers. However, short blood circulation time, large-size-induced insufficient tumor accumulation and penetration into tumor parenchyma, as well as limited cellular internalization by tumor cells and cancer stem cells (CSCs), and difficult intracellular drug release restrict the anticancer activity of tumor-cell-derived MP-based drug-delivery systems. In this work, hydrophobicity-adaptive polymers based on poly(N-isopropylacrylamide) are anchored to tumor-cell-derived MPs for enhanced delivery of the anticancer drug doxorubicin (DOX). The polymers are hydrophilic in blood to prolong the circulation time of DOX-loaded MPs (DOX@MPs), while rapidly switching to hydrophobic at the tumor acidic microenvironment. The hydrophobicity of polymers drives the fission of tumor-cell-derived MPs to form small vesicles, facilitating tumor accumulation, deep tumor penetration, and efficient internalization of DOX@MPs into tumor cells and CSCs. Subsequently, the hydrophobicity of polymers in acidic lysosomes further promotes DOX release to nuclei for strong cytotoxicity against tumor cells and CSCs. The work provides a facile and simple strategy for improved anticancer drug delivery of tumor-cell-derived MPs.

Bone Lesion-Derived Extracellular Vesicles Fuel Prometastatic Cascades in Hepatocellular Carcinoma by Transferring ALKBH5-Targeting miR-3190-5p.

Bone is the second leading metastatic site for hepatocellular carcinoma (HCC). Patients with HCC and bone metastasis suffer poor quality of life and reduced survival time. Extracellular vesicles (EVs) are widely involved in HCC formation and metastasis. However, the communication between primary HCC and bone lesions mediated by EVs remains unclear and the possible effect of bone metastasis on the progression of HCC remains largely unknown. Here, bone-metastasized HCC-derived EVs (BM-EVs) are found to localize to orthotropic HCC cells and promote HCC progression. Mechanistically, miR-3190-5p (miR-3190) is upregulated in intracellular HCC cells isolated from bone lesions as well as in their derived EVs. miR-3190 in BM-EVs is transferred into orthotopic tumor cells and enhances their metastatic capacity by downregulating AlkB homolog 5 (ALKBH5) expression. Decreased level of ALKBH5 exacerbates the prometastatic characteristics of HCC by modulating gene expression in N6-methyladenosine-dependent and -independent ways. Finally, antagomir-miR-3190-loaded liposomes with HCC affinity successfully suppress HCC progression in mice treated with BM-EVs. These findings reveal that BM-EVs initiate prometastatic cascades in orthotopic HCC by transferring ALKBH5-targeting miR-3190 and miR-3190 is serving as a promising therapeutic target for inhibiting the progression of HCC in patients with bone metastasis.

Extracellular vesicles for improved tumor accumulation and penetration.

Extracellular vesicles (EVs), including microparticles and exosomes, have emerged as potential tools for tumor targeting delivery during the past years. Recently, mass of strategies are applied to assist EVs to accumulate and penetrate into deep tumor sites. In this review, EVs from different cells with unique innate characters and engineered approaches (e.g. chemical engineering, genetical engineering and biomimetic engineering) as drug delivery systems to enhance tumor accumulation and penetration are summarized. Meanwhile, efficient biological function modulation (e.g. extracellular matrix degradation, mechanical property regulation and transcytosis) is introduced to facilitate tumor accumulation and penetration of EVs. Finally, the prospects and challenges on further clinical applications of EVs are discussed.

Biodegradable electrospun nanofibrous platform integrating antiplatelet therapy-chemotherapy for preventing postoperative tumor recurrence and metastasis.

The perioperative trauma-related platelet recruitment and activation severely affect tumor recurrence and metastasis. Therefore, efficiently killing residual tumor cells and simultaneously inhibiting platelet activation to block platelet-cancer cell interaction might be a promising strategy to prevent postoperative tumor recurrence and metastasis. Methods: Biodegradable PLGA electrospun nanofibrous films co-delivering doxorubicin-loaded tumor repopulating cell-derived microparticles (DOX-MPs) and aspirin (ASA) were developed as the implant materials (DOX-MPs/ASA@NF) for postoperative in-situ treatment. The characterization, cytotoxicity against tumor cells, inhibition in platelet activation-triggered proliferation, migration and metastasis of tumor cells and in vivo anti-recurrence and anti-metastasis activity induced by DOX-MPs/ASA@NF were systematically evaluated. Results: PLGA nanofibrous films facilitate the enhanced distribution of DOX-MPs as well as DOX-MPs and ASA release in a time-programmed manner within the tumor resection cavity. The released DOX-MPs efficiently kill the residual tumor cells, while ASA decreases platelet activation and inhibits platelet-promoted proliferation, migration and metastasis of tumor cells, resulting in the remarkable inhibition of postoperative tumor recurrence and metastasis. Conclusions: DOX-MPs/ASA@NF may be a promising candidate to prevent the recurrence and metastasis of resectable tumors.

Reversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts.

Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8+ T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8+ T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8+ T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment.

Effect of in vitro simulated gastrointestinal digestion on the antioxidant activity, molecular weight, and microstructure of polysaccharides from Chinese yam.

In this study, we investigated the antioxidant properties and the changes of molecular weight (Mw), antioxidant activity, and microstructure of Chinese yam polysaccharides (CYP-A) during in vitro digestion. Results showed that the scavenging rate of 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical of CYP-A was approximately 79% at the concentration of 6 mg/mL. Furthermore, the antioxidant ability positively correlated with the concentration of CYP-A. In addition, the Mw of CYP-A decreased (p < 0.05) after intestinal digestion. Fourier transform infrared showed that the degrees of esterification of CYP-A increased to 39.04% after 6 h of gastric digestion. Moreover, the structure of CYP-A changed after in vitro gastric digestion. The scanning electron microscope (SEM) images indicated that the surface morphology of CYP-A turned from smooth and irregular to a layered honeycomb after gastrointestinal digestion in vitro. Surprisingly, the activity of DPPH radical scavenging significantly increased (p < 0.05) in the intestinal digested samples of CYP-A, which showed a positive correlation with the concentration of CYP-A. However, the reducing power significantly decreased (p < 0.05) after in vitro intestinal digestion.

The impact of a novel Chinese yam-derived polysaccharide on blood glucose control in HFD and STZ-induced diabetic C57BL/6 mice.

Chinese yam, as a kind of traditional "medicine and food homologous food" in Asia, could assistance to digestion, nourish the lungs and relieve cough. Some research also suggested that Chinese yam could prevention of hyperglycemia, but the specific mechanism of action was not clear. In this paper, an acidic polysaccharide (CYPB) was isolated from Chinese yam with the molecular weight of 1.55 × 102 kDa. The determination of the monosaccharide composition of CYPB with ion chromatography showed that CYPB was composed of rhamnose, glucose, arabinose, galactose, glucose, xylose and glucuronic acid with the ratio of 6 : 3.73 : 7.31 : 10.95 : 4.56 : 1. The structural analysis indicated that the CYPB contain 1 → 3, 1 → 4, 1 → 2, 1 → 6 and 1 → 3, 6 glycoside bonds. The experimental results of diabetic mice model induced by high-fat diet (HFD) and streptozocin (STZ) indicated that CYPB could improve clinical symptoms and alleviate the glucose tolerance damage symptoms effectively. The underlying mechanism of regulate blood glucose of CYPB may be related to improve the ability of synthesize glycogen, insulin resistance and reduce gluconeogenesis by regulating the expression of InsR, PI3K, Akt and FoxO3, GLUT4 proteins in PI3K/Akt signaling pathway in T2DM mice.

Protective effect and mechanism of docosahexaenoic acid on the cognitive function in female APP/PS1 mice.

Docosahexaenoic acid (DHA) has been studied for many years owing to its protective effect on the decline in brain function. DHA intake reduces the risk of Alzheimer's disease (AD) and decreases amyloid deposition; however, the underlying molecular mechanism has not been completed elucidated. In this study, the effect of DHA on the cognitive function of amyloid precursor protein (APP)/PS1 in wild-type mice and its related mechanism were investigated. Results from the Morris water maze test showed that DHA improved learning and memory function in mice. Moreover, DHA reduced neuronal damage in mice brains, as determined using Nissl staining. Unsaturated fatty acid levels in the brain of mice increased (p < 0.01) after DHA administration and saturated fatty acid levels decreased (p < 0.01). The deposition of amyloid-beta (Aß) plaques and tau protein neurofibrillary tangles was significantly inhibited. The mechanism of action of DHA was attributed to the upregulation of the expression of ß-secretase (BACE)2, which competed with BACE1 to cleave APP, thus decreasing the production of extracellular Aß fragments (p < 0.01). The expression level of insulin-degrading enzyme was not significantly different. The expression of N-methyl-D-aspartate receptors was further downregulated and the phosphorylation of glycogen synthase kinase-3ß and tau protein was inhibited (p < 0.01). These data indicated that DHA could protect cognitive function in mice by reducing Aß plaque formation and decreasing tau phosphorylation levels.

The Protective Effect of Docosahexaenoic Acid on PC12 Cells in Oxidative Stress Induced by H2O2 through the TrkB-Erk1/2-CREB Pathway.

Docosahexaenoic acid (DHA) has attracted plenty of interest in the prevention of neurodegenerative diseases. Although the beneficial effects of DHA on the central nervous system function are recognized, more information on the molecular mechanisms involved in its neuroprotective effects is required. The present study aimed to evaluate the effects of DHA on the function of mitochondria, neurite growth-related proteins signaling pathway, and neural signal transmission. In this study, PC12 cells were treated with H2O2 (400 µM) to establish an oxidative damage model. Results showed that DHA improved the viability and morphology of PC12 cells. DHA significantly increased the antioxidant capacity, mitochondrial membrane potential, and activity of ATPase in the cells. Furthermore, the phosphorylation levels of tyrosine kinase receptor (BTrkB), phospholipase C-γ1 (PLCγ1), calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), and cAMP-response element-binding protein (CREB) were upregulated by DHA. The damage on F-actin induced by H2O2 was reversed by DHA, indicating that DHA could protect neurite outgrowth. In addition, DHA increased the content of acetylcholine and γ-aminobutyric acid while decreasing glutamic acid. These results revealed that DHA could protect PC12 cells from damage induced by H2O2 through the TrkB-ERK1/2-CREB pathway.

Regulatory effect of non-starch polysaccharides from purple sweet potato on intestinal microbiota of mice with antibiotic-associated diarrhea.

Antibiotic treatment causes antibiotic-associated diarrhea (AAD), which is usually accompanied by disorders of the intestinal flora, aggravating the patient's condition. Recently, more attention has been devoted to the ability of plant polysaccharides to improve the body's flora and enhance immunity. However, reports on whether purple sweet potato polysaccharides (PSPPs) can improve AAD are scarce. This study aimed to extract a non-starch polysaccharide from purple sweet potato and analyze its structure and ability to regulate the intestinal flora of mice with AAD. The diarrhea model was established via intragastric administration of lincomycin and different concentrations of PSPPs (0.1 g kg-1, 0.2 g kg-1, and 0.4 g kg-1) to Balb/C mice. The results showed that PSPP was a pyran polysaccharide with 1 → 2, 1 → 2, 6, 1 → 4, 1 → 4, 6 glycosidic bonds in an α-configuration. In vivo experiments showed that PSPP could relieve diarrhea and improve the structural damage in the ileum caused by lincomycin hydrochloride. In addition, treatment with PSPPs decreased the levels of IL-1ß, IL-6 and TNF-α but increased the level of IL-10 in the intestines of mice (p < 0.01). The results of 16S rRNA sequencing showed that PSPPs changed the composition and diversity of the intestinal flora of mice with AAD. In addition, PSPP treatment increased the content of short-chain fatty acids (p < 0.01). These results revealed that PSPPs regulated the intestinal flora, balanced fatty acid metabolism, and relieved the symptoms of diarrhea to a certain extent in mice.

Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles.

The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8+ T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8+ T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.

The immunomodulatory effect of docosahexaenoic acid (DHA) on the RAW264.7 cells by modification of the membrane structure and function.

BACKGROUND: DHA can regulate various physiological functions of cells. Our group has clarified the immunomodulatory activity and molecular mechanism of DHA on RAW264.7 cells. However, the effect of DHA on the membrane fatty acid environment and the activation of signaling pathways on the cell membrane is still not clear. METHODS: In this study, we evaluated the fluidity, the potential and the fatty acid, phospholipid and protein composition of the RAW264.7 cell membrane by DHA treatment. RESULTS: The fluidity of the RAW264.7 cell membrane was increased by DHA treatment. The results of membrane potential analysis suggested that DHA (2.4 µM) significantly reduced the surface potential of the cell membrane, which might influence the fluidity of cell membranes. In addition, the fatty acids and phospholipids were measured and the results indicated that DHA treatment (2.4 µM) altered the lipid environment and the composition of phospholipids on the RAW264.7 cell membrane. Then the LC-MS/MS-based label free quantitative proteomics approach was applied to identify a total of 86 differential proteins in the 2.4 µM DHA and control groups (>2.0-fold change or <0.5-fold change in protein expression); these proteins are most frequently related to the cell response to stimuli and the response to stress. These results suggested that DHA could alter the fluidity, the potential, the fatty acid and phospholipid composition of the RAW264.7 cell membrane, eventually affecting the proteins of the cell membrane, especially the changes in Siglec 1, iNOS, GPR120, Ras and MEK expressions (validated by western blot analysis), which are likely associated with the activation of the intracellular signaling pathway in RAW264.7 cells by DHA treatment.

A polysaccharide from Grifola frondosa fruit body induces HT-29 cells apoptosis by PI3K/AKT-MAPKs and NF-κB-pathway.

BACKGROUND: A neutral polysaccharide was isolated from the fruiting body of a mushroom Grifola frondosa (GFP-A). The tumor suppressive activity of GFP-A on protein expressions of PI3K/AKT, MAPKs, nuclear factor κB and caspase pathways in HT-29 cells were investigated. METHODS: The inhibitory effect and mechanism of GFP-A on the HT-29 cells were investigated. The cell viability was examined by MTT. Scanning electron microscopy analysis and flow cytometry were conducted to examine the apoptosis of cells. The protein expressions of PI3K/AKT, MAPKs, nuclear factor κB and caspase pathways were analyzed using western blot. RESULTS: The results of MTT assay showed that GFP-A of 180 µg/mL could significantly inhibit the proliferation of HT-29 cells. Western blotting results showed that GFP-A decreased the protein expression of PI3K and AKT, enhanced the phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK and inhibited the phosphorylation of ERK1/2 and the translocation of nuclear factor-κB (NF-κB) into the nucleus. In the meanwhile, GFP-A could up-regulate the ratio of Bax to Bcl-2, increase the release of cytochrome C to cytoplasm, ultimately lead to the activation of caspase-9. CONCLUSIONS: The above results confirmed that GFP-A promoted the apoptosis of HT-29 cells through PI3K/AKT-MAPKs-NF-κB and caspase signaling pathways.

Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy.

Developing biomimetic nanoparticles without loss of the integrity of proteins remains a major challenge in cancer chemotherapy. Here, we develop a biocompatible tumor-cell-exocytosed exosome-biomimetic porous silicon nanoparticles (PSiNPs) as drug carrier for targeted cancer chemotherapy. Exosome-sheathed doxorubicin-loaded PSiNPs (DOX@E-PSiNPs), generated by exocytosis of the endocytosed DOX-loaded PSiNPs from tumor cells, exhibit enhanced tumor accumulation, extravasation from blood vessels and penetration into deep tumor parenchyma following intravenous administration. In addition, DOX@E-PSiNPs, regardless of their origin, possess significant cellular uptake and cytotoxicity in both bulk cancer cells and cancer stem cells (CSCs). These properties endow DOX@E-PSiNPs with great in vivo enrichment in total tumor cells and side population cells with features of CSCs, resulting in anticancer activity and CSCs reduction in subcutaneous, orthotopic and metastatic tumor models. These results provide a proof-of-concept for the use of exosome-biomimetic nanoparticles exocytosed from tumor cells as a promising drug carrier for efficient cancer chemotherapy.

The softness of tumour-cell-derived microparticles regulates their drug-delivery efficiency.

Extracellular microparticles (MPs) can function as drug-delivery vehicles for anticancer drugs. Here, we show that the softness of MPs derived from tumour-repopulating cells (TRCs) isolated from three-dimensional fibrin gels enhances the MPs' drug-delivery efficiency. We found that, compared with MPs derived from tumour cells cultured in conventional tissue-culture plastic, TRC-derived MPs intravenously injected in tumour-xenograft-bearing mice showed enhanced accumulation in tumour tissues, enhanced blood-vessel crossing and penetration into tumour parenchyma, and preferential uptake by highly tumorigenic TRCs. We also show that the cytoskeleton-related protein cytospin-A plays a critical role in the regulation of TRC-derived MP softness. The modulation of the mechanical properties of TRC-derived MPs could aid the efficiency of delivery of anticancer drugs.

A Biomimetic Gold Nanocages-Based Nanoplatform for Efficient Tumor Ablation and Reduced Inflammation.

Gold nanocages (AuNCs), with high photothermal conversion efficiency and unique hollow interiors, have become a promising nanoplatform for synergistic phototheraml therapy (PTT)-chemotherapy. However, the insufficient tumor targeting, in vivo premature drug leakage and low drug loading efficiency responsible for the spatial-temporal un-synchronization of PTT-chemotherapy, as well as inflammatory response might compromise the anticancer treatment of AuNCs-based drug delivery systems. Methods: Cancer cell membrane (CCM)-coated AuNCs were developed to load anticancer drug doxorubicin (DOX@CAuNCs) by transmembrane ammonium sulfate gradient method. In vitro and in vivo analysis, including characterization, macrophage phagocytosis and tumor targeting capacity, near-infrared (NIR) laser-induced drug release, antitumor efficacy and inflammation response were systematically performed. Results: DOX@CAuNCs showed a high DOX loading capacity and on-demand NIR laser-triggered DOX release compared with CAuNCs passively loading DOX by electrostatic adsorption, a commonly used method to load drug to AuNCs. Meanwhile, in view of the properties of CCM coated on AuNCs, DOX@CAuNCs exhibited decreased macrophage phagocytosis, prolonged blood circulation and enhanced internalization by cancer cells, generating preferable tumor targeting ability. With these integrated advantages, DOX@CAuNCs demonstrated highly efficient and precise spatial-temporal synchronization of PTT-chemotherapy, achieving complete tumor ablation with no obvious side effects. Besides, coating with CCM significantly alleviated AuNCs-induced inflammatory response. Conclusion: This biomimetic AuNCs-based platform might be a prospective drug delivery system for precision PTT and chemotherapy, acquiring desired cancer treatment efficacy and low inflammatory response.