AbstractThe limited efficacy of cancer immunotherapy occurs due to the lack of spatiotemporal orchestration of adaptive immune response stimulation and immunosuppressive tumor microenvironment modulation. Herein, we report a nanoplatform fabricated using a pH-sensitive triblock copolymer synthesized by reversible addition-fragmentation chain transfer polymerization enabling in situ tumor vaccination and tumor-associated macrophages (TAMs) polarization.

摘要由于缺乏适应性免疫应答刺激和免疫抑制性肿瘤微环境调节的时空协调，癌症免疫疗法的疗效有限。在此，我们报道了使用通过可逆加成-断裂链转移聚合合成的pH敏感三嵌段共聚物制造的纳米平台，其能够原位肿瘤疫苗接种和肿瘤相关巨噬细胞（TAM）极化。

The nanocarrier itself can induce melanoma immunogenic cell death (ICD) via tertiary amines and thioethers concentrating on mitochondria to regulate metabolism in triggering endoplasmic reticulum stress and upregulating gasdermin D for pyroptosis as well as some features of ferroptosis and apoptosis.

纳米载体本身可以通过集中在线粒体上的叔胺和硫醚诱导黑色素瘤免疫原性细胞死亡（ICD），以调节代谢，触发内质网应激并上调gasdermin D的pyroptosis以及ferroptosis和凋亡的一些特征。

After the addition of ligand cyclic arginine-glycine-aspartic acid (cRGD) and mannose, the mixed nanocarrier with immune adjuvant resiquimod encapsulation can target B16F10 cells for in situ tumor vaccination and TAMs for M1 phenotype polarization. In vivo studies indicate that the mixed targeting nanoplatform elicits tumor ICD, dendritic cell maturation, TAM polarization, and cytotoxic T lymphocyte infiltration and inhibits melanoma volume growth.

在加入配体环精氨酸-甘氨酸-天冬氨酸（cRGD）和甘露糖后，具有免疫佐剂瑞喹莫特包封的混合纳米载体可以靶向B16F10细胞用于原位肿瘤疫苗接种和用于M1表型极化的TAM。体内研究表明，混合靶向纳米平台引发肿瘤ICD，树突状细胞成熟，TAM极化和细胞毒性T淋巴细胞浸润，并抑制黑素瘤体积生长。

In combination with immune checkpoint blockade, the survival time of mice is markedly prolonged. This study provides a strategy for utilizing immunoactive materials in the innate and adaptive immune responses to augment cancer therapy..

结合免疫检查点阻断，小鼠的存活时间显着延长。这项研究提供了一种在先天性和适应性免疫反应中利用免疫活性物质来增强癌症治疗的策略。。

IntroductionCancer immunotherapy is one of the most promising strategies for tumor treatment and has attracted extensive attention. Induction of tumor immunogenic cell death (ICD) is a widely used methodology in which tumor cells, after encountering external stimuli, can change from a non-immunogenic state to an immunogenic state with host immune response provocation1,2,3.

引言癌症免疫治疗是最有前途的肿瘤治疗策略之一，已引起广泛关注。诱导肿瘤免疫原性细胞死亡（ICD）是一种广泛使用的方法，其中肿瘤细胞在遇到外部刺激后，可以通过宿主免疫应答激发从非免疫原性状态变为免疫原性状态1,2,3。

The typical immune features of ICD are damage-associated molecular patterns (DAMPs) (e.g., calreticulin [CRT], high mobility group box 1 [HMGB1], and adenosine triphosphate [ATP]) secretion4,5 and tumor-associated antigen release that can facilitate dendritic cell (DC) maturation, migration, and antigen presentation to T cells for host immunity activation6,7.

ICD的典型免疫特征是损伤相关分子模式（DAMPs）（例如钙网蛋白[CRT]，高迁移率族蛋白1[HMGB1]和三磷酸腺苷[ATP]）分泌4,5和肿瘤相关抗原释放，可促进树突状细胞（DC）成熟，迁移和抗原呈递给T细胞以激活宿主免疫6,7。

Currently, various strategies, including photodynamic therapy, chemotherapy, and pyroptosis, have been developed for ICD-mediated tumor immunotherapy1,8,9,10,11,12,13,14,15. However, these methodologies generally require additional ICD inducers that may complicate the nanoplatform. Therefore, the development of nanocarriers that can directly induce ICD is imperative to simultaneously simplify nanoformulations to ensure therapeutic efficacy due to their own immunity.Tumor vaccines have emerged as a promising strategy for long-term cancer immunotherapy, and they primarily attack tumors via eliciting an antigen-specific immune response16.

目前，已经为ICD介导的肿瘤免疫治疗开发了各种策略，包括光动力疗法，化疗和pyroptosis[1,8,9,10,11,12,13,14,15]。然而，这些方法通常需要额外的ICD诱导剂，这可能会使纳米平台复杂化。因此，可以直接诱导ICD的纳米载体的开发对于同时简化纳米制剂以确保由于其自身免疫而产生的治疗功效是必不可少的。肿瘤疫苗已成为长期癌症免疫治疗的一种有前途的策略，它们主要通过引发抗原特异性免疫反应来攻击肿瘤16。

Although there are definite antigens in tumor vaccines, the heterogeneity and high cost of mutant antigen identification have restricted their further development17,18. To cope with the above issues, in situ tumor vaccination can be greatly enhanced via combining immune adjuvants with tumor-associated antigens (TAAs) that can be directly released by dying tumor cells in vivo after different treatments (e.g., photod.

尽管肿瘤疫苗中存在明确的抗原，但突变抗原鉴定的异质性和高成本限制了它们的进一步发展17,18。为了解决上述问题，通过将免疫佐剂与肿瘤相关抗原（TAA）组合，可以大大增强原位肿瘤疫苗接种，肿瘤相关抗原可以在不同处理（例如photod）后由体内死亡的肿瘤细胞直接释放。

To target B16F10 cells and TAMs separately, cRGD- and Man-targeting ligands were decorated onto the nanocarrier surface to obtain cRGD-pRNCThioether+DEA and Man-pRNCThioether+DEA, respectively. c(RGDfK) is a cyclic peptide that can target tumor cells (e.g., B16F10 cells, LLC cells) with high expression of αvβ3, and Man is a cyclic monosaccharide that targets TAMs with high mannose receptor expression45,46,47.

为了分别靶向B16F10细胞和TAM，将cRGD和Man靶向配体修饰到纳米载体表面上，分别获得cRGD-PrNC硫醚+DEA和Man-PrNC硫醚+DEA。c（RGDfK）是一种环肽，可以靶向具有高表达αvβ3的肿瘤细胞（例如B16F10细胞，LLC细胞），而Man是一种环状单糖，其靶向具有高甘露糖受体表达的TAM 45,46,47。

The synthesis of cRGD (Man)-PEG-PMMA-PPPMA was similar to that of PEG-PMMA-PPPMA (Supplementary Fig. 29). The ratios of c(RGDfK) and Man were 85% and 87%, respectively, based on peaks of methylene protons in PEG (δ, 3.63 ppm), methylene protons (δ, 1.84 ppm) in cRGD (Supplementary Fig. 30), and methine proton (δ, 2.28 ppm) in Man according to 1H NMR results (Supplementary Fig. 31).cRGD-pRNCThioether+DEA and Man-pRNCThioether+DEA were also fabricated via the solvent-exchange method.

cRGD（Man）-PEG-PMMA-PPPMA的合成类似于PEG-PMMA-PPPMA的合成（补充图29）。基于PEG中亚甲基质子（δ，3.63ppm），cRGD中亚甲基质子（δ，1.84ppm）的峰，c（RGDfK）和Man的比例分别为85%和87%（补充图30），根据1H NMR结果（补充图31），人中的亚甲基质子（δ，2.28ppm）。cRGD-PrNChiothere+DEA和Man-PrNChiothere+DEA也通过溶剂交换法制造。

DLS results indicated that their diameter sizes were 168.0 ± 4.85 nm and 143.5 ± 1.08 nm, respectively, and PDI was 0.16 ± 0.016 and 0.23 ± 0.021 (Fig. 4a, b, Supplementary Table 3). After mixing, cRGD- mix Man-pRNCThioether+DEA was obtained, and no obvious changes were detected (Supplementary Fig. 32 and Supplementary Table 3).

DLS结果表明，它们的直径分别为168.0±4.85 nm和143.5±1.08 nm，PDI为0.16±0.016和0.23±0.021（图4a，b，补充表3）。混合后，获得cRGD-mix-Man-PrNCthiotether+DEA，未检测到明显变化（补充图32和补充表3）。

According to Fig. 2f, the concentration of pRNCThioether+DEA as the ICD inducer was chosen as 100 μg/mL due to the obvious CRT exposure, and this concentration was also suitable for cRGD-pRNCThioether+DEA. According to Fig. 4c, the cell viability of RAW264.7 cells was 88 ± 2.8% when the Man-pRNCThioether+DEA concentration was 50 μg/mL, while the value decreased to 73 ± 2.6% when the concentration was increased to 100 μg/mL.

根据图2f，由于明显的CRT暴露，选择作为ICD诱导剂的PrNChiotheter+DEA的浓度为100μg/mL，并且该浓度也适用于cRGD-PrNChiotheter+DEA。根据图4c，当Man-PRN硫醚+DEA浓度为50μg/mL时，RAW264.7细胞的细胞活力为88±2.8%，而当浓度增加到100μg/mL时，该值降至73±2.6%。

Thus, to reduce macrophage death the concentration of Man-pRNCThioether+DEA was selected as 50 μg/mL. cRGD (Man)-pRNCThioether+DEA with R848 .

因此，为了减少巨噬细胞死亡，选择Man-PrnC硫醚+DEA的浓度为50μg/mL。具有R848的cRGD（Man）-PrnC硫醚+DEA。

R848 was replaced with FITC to better monitor intracellular internalization that was characterized by FCM. As presented in Fig. 4f, a more obvious fluorescence shift and cytotoxicity were observed in B16F10 cells in response to cRGD-pRNCThioether+DEA@FITC treatment than that in response to pRNCThioether+DEA@FITC, thus indicating the good targetability of cRGD (Supplementary Figs. 35, 37).

R848被FITC取代，以更好地监测以FCM为特征的细胞内内化。+DEA@FITC比PRNC硫醚治疗更有效+DEA@FITC，因此表明cRGD具有良好的靶向性（补充图35,37）。

After Man-pRNCThioether+DEA@FITC treatment, a stronger fluorescence shift and cytotoxicity were observed in RAW264.7 cells compared to the pRNCThioether+DEA@FITC group, thus indicating noticeable targetability of Man (Fig. 4g, Supplementary Fig. 36). The CLSM results in Supplementary Fig. 38 indicated that cRGD and Man decoration enhanced the targetability of B16F10 and RAW264.7, respectively.cRGD-pRNCThioether+DEA@R848 mediated DCs maturationTo test if the nanocarrier could activate DCs in vitro, we first examined its ability to induce ICD in B16F10 cells as characterized by FCM.

在Man PRNC硫醚之后+DEA@FITC处理后，与PRNC硫醚相比，RAW264.7细胞的荧光位移和细胞毒性更强+DEA@FITC组，因此表明人类具有明显的靶向性（图4g，补充图36）。补充图38中的CLSM结果表明，cRGD和Man装饰分别增强了B16F10和RAW264.7的靶向性。cRGD-PrNCthiotether+DEA@R848介导的DC成熟测试如果纳米载体可以在体外激活DC，我们首先检查了其在B16F10细胞中诱导ICD的能力，如FCM所表征的。

An elevated CRT+ ratio was observed in cells treated with cRGD-pRNCThioether+DEA or cRGD-pRNCThioether+DEA@R848 compared to that of NCMMA and PBS. Negligible differences were observed among the cRGD-pRNCThioether+DEA, cRGD-pRNCThioether+DEA@R848, and cRGD- mix Man-pRNCThioether+DEA@R848 treated groups, thus indicating that cRGD-pRNCThioether+DEA induced ICD while R848 did not and that the mixing of cRGD- and Man-nanoformulations did not affect the ICD inducibility of cRGD-pRNCThioether+DEA (Supplementary Fig. 39).

在用cRGD-PrNC硫醚+DEA或cRGD-PrNC硫醚处理的细胞中观察到CRT+比率升高+DEA@R848与NCMMA和PBS相比，cRGD-PrNC硫醚+DEA，cRGD-PrNC硫醚之间的差异可忽略不计+DEA@R848，和cRGD-混合Man-PrnC硫醚+DEA@R848治疗组，因此表明cRGD-PrNC硫醚+DEA诱导ICD，而R848不诱导ICD，并且cRGD和Man纳米制剂的混合不影响cRGD-PrNC硫醚+DEA的ICD诱导性（补充图39）。

When B16F10 cell supernatant was added into DCs, it was observed that both cRGD-pRNCThioether+DEA (CD11c+CD80+: 20.30 ± 2.25%; CD11c+CD86+: 23.60 ± 2.95%) and cRGD-pRNCThioether+DEA@R848 (CD11c+CD80+: 19.80 ± 0.20%; CD11c+CD86+: 23.30 ± 0.36%) treated cancer cells displayed a notable DC maturation c.

当将B16F10细胞上清液加入DC中时，观察到cRGD-PRNC硫醚+DEA（CD11c+CD80+：20.30±2.25%；CD11c+CD86+：23.60±2.95%）和cRGD-PrNC硫醚+DEA@R848（CD11c+CD80+：19.80±0.20%；CD11c+CD86+：23.30±0.36%）处理的癌细胞显示出显着的DC成熟c。

To avoid fluorescence interference from melanoma, B16F10 cells were replaced with LLC cells to construct a tumor model in C57BL/6 mice for in vivo targeting of cRGD-pRNCThioether+DEA and Man-pRNCThioether+DEA via a near-infrared (NIR) in vivo imaging system (IVIS), FCM, and immunofluorescence staining analysis.

为了避免来自黑素瘤的荧光干扰，将B16F10细胞替换为LLC细胞以在C57BL/6小鼠中构建肿瘤模型，用于通过近红外（NIR）体内成像系统（IVIS），FCM和免疫荧光染色分析体内靶向cRGD-PrNChiotheter+DEA和Man-PrNChiotheter+DEA。

cRGD-pRNCThioether+DEA was loaded with DID to form cRGD-pRNCThioether+DEA/DID, and Man-pRNCThioether+DEA was encapsulated in DIR to form Man-pRNCThioether+DEA/DIR (Fig. 5a).Fig. 5: Investigation of mixed nanoformulations for targeting both tumor cells and TAMs in vivo.a Schematic illustration of mixed nanoformulation preparation, drug administration and analysis.

将cRGD-PrNC硫醚+DEA加载DID以形成cRGD-PrNC硫醚+DEA/DID，并将Man-PrNC硫醚+DEA包封在DIR中以形成Man-PrNC硫醚+DEA/DIR（图5a）。图5：用于体内靶向肿瘤细胞和TAM的混合纳米制剂的研究。混合纳米制剂制备，药物施用和分析的示意图。

b In vivo fluorescence imaging after tail vein injection of different formulations for cRGD targeting investigation. c Quantitative analysis of fluorescence signals at 24 h post-treatment (n = 3 mice per group). d Representative ex vivo images of tumor tissues after treatments at 24 h. e Representative flow cytometric images and quantification of DID+ in PD-L1+ tumor cells in vivo (n = 3 mice per group).

b尾静脉注射不同制剂用于cRGD靶向研究后的体内荧光成像。c治疗后24小时荧光信号的定量分析（每组n=3只小鼠）。d在24小时处理后肿瘤组织的代表性离体图像。代表性流式细胞术图像和体内PD-L1+肿瘤细胞中DID+的定量（每组n=3只小鼠）。

f In vivo fluorescence imaging after tail vein injection of different formulations for Man targeting investigation. g Quantitative analysis of fluorescence signals at 24 h (n = 3 mice per group). h Representative ex vivo images of tumor tissues. i Representative flow cytometric images and semi-quantification analysis of DIR+ in F4/80+ TAMs cells in vivo (n = 3 mice per group).

f尾静脉注射不同制剂后的体内荧光成像用于Man靶向研究。g 24小时荧光信号的定量分析（每组n=3只小鼠）。h肿瘤组织的代表性离体图像。i体内F4/80+TAMs细胞中DIR+的代表性流式细胞术图像和半定量分析（每组n=3只小鼠）。

Data are presented as mean ± SD. Statistical significance was calculated through one-way ANOVA for multiple comparisons using a Tukey post-hoc test.Full size imageFor the cRGD nanoformulations, after intravenous (i.v.) injection the in vivo fluorescence intensity within the 24 h first increased and then decreased, and it reached a .

数据表示为平均值±SD。使用Tukey事后检验通过单因素方差分析计算统计学显着性，用于多重比较。。

Tumor cells death was determined by flow cytometry. First, B16F10 cells (2.0 × 105/well) were seeded into a six-well plate and grown overnight. PBS, NCMMA, pRNCThioether+DEA, pRNCThioether+DEA + Z-VAD-FMK, pRNCThioether+DEA +Nec-1s, and pRNCThioether+DEA + Fer-1 were separately added into each well for 48 h incubation.

通过流式细胞术测定肿瘤细胞死亡。首先，将B16F10细胞（2.0×105/孔）接种到六孔板中并生长过夜。将PBS，NCMMA，pRNCThioether+DEA，pRNCThioether+DEA+ Z-VAD-FMK，pRNCThioether+DEA+Nec-1s和pRNCThioether+DEA+Fer-1分别加入每个孔中孵育48小时。

Cells were digested by trypsin and subsequently washed with PBS (×3). Cell death was assessed by flow cytometry using an Annexin V/PI cell assay kit (Biosharp) via the protocol provided by the manufacturer.Intracellular lipid peroxide detectionFirst, B16F10 cells (2.0 × 105/well) were seeded into a six-well plate and cultured overnight.

用胰蛋白酶消化细胞，然后用PBS（×3）洗涤。使用膜联蛋白V/PI细胞测定试剂盒（Biosharp），通过制造商提供的方案，通过流式细胞术评估细胞死亡。细胞内脂质过氧化物检测首先，将B16F10细胞（2.0×105/孔）接种到六孔板中并培养过夜。

Phosphate-buffered saline (PBS), NCMMA, and pRNCThioether+DEA were added to each well and incubated for 24 h. After incubation for 24 h, the culture medium was removed, cells were washed 3 times with PBS, and C11-BIODPY (1 mL, 10 μM, serum-free 1640 medium was used) was added to each well for 30 min incubation away from light in a cell incubator.

将磷酸盐缓冲盐水（PBS），NCMMA和pRNCThioether+DEA加入每个孔中并孵育24小时。孵育24小时后，除去培养基，用PBS洗涤细胞3次，并将C11-BIODPY（1ml，10μM，使用无血清1640培养基）加入每个孔中，在细胞培养箱中避光孵育30分钟。

The cells were then digested with trypsin and washed three times with PBS. The cells were suspended in PBS (0.5 mL) and detected using flow cytometry.Synthesis of Man (cRGD)-PEG-PMMA-PPPMAMan-PEG-PMMA-PPPMA was obtained by the amidation of COOH-PEG-PMMA-PPPMA and Man-NH2. The synthesis of COOH-PEG-PMMA-PPPMA was similar to that of PEG-PMMA-PPPMA, and the molecular weights was determined by 1H NMR spectroscopy.

然后将细胞用胰蛋白酶消化并用PBS洗涤三次。将细胞悬浮于PBS（0.5mL）中并使用流式细胞术检测。Man（cRGD）-PEG-PMMA-PPPMA的合成通过COOH-PEG-PMMA-PPPMA和Man-NH2的酰胺化获得Man-PEG-PMMA-PPPMA。COOH-PEG-PMMA-PPPMA的合成类似于PEG-PMMA-PPPMA的合成，并且通过1H NMR光谱测定分子量。

To obtain Man-PEG-PMMA-PPPMA, NHS (0.489 mg, 0.0043 mmol) and EDC·HCl (0.815 mg, 0.0043 mmol) were first added into the mixture solution of COOH-PEG-PMMA-PPPMA (35 mg, 0.0028 mmol) and triethylamine (TEA) with stirring for 1.5 h under N2 to acquire NHS-PEG-PMMA-PPPMA. In the ice water bath and N2 atmosphere, NHS-PEG-PMMA-PPPMA was added dropwise to a Man-NH2 solution contain.

为了获得Man-PEG-PMMA-PPPMA，首先将NHS（0.489mg，0.0043mmol）和EDC·HCl（0.815mg，0.0043mmol）加入到COOH-PEG-PMMA-PPPMA（35mg，0.0028mmol）和三乙胺（TEA）的混合溶液中，在N2下搅拌1.5h，得到NHS-PEG-PMMA-PPPMA。在冰水浴和N2气氛中，将NHS-PEG-PMMA-PPPMA滴加到含有Man-NH2的溶液中。

(1)

(1)

$${{{\rm{DLE}}}}={{{\rm{mass}}}}\; {{{\rm{of}}}}\; {{{\rm{actual}}}}\; {{{\rm{drug}}}}\; {{{\rm{encapsulation}}}}/{{{\rm{mass}}}}\; \\ {{{\rm{of}}}}\; {{{\rm{theoretical}}}}\; {{{\rm{drug}}}}\; {{{\rm{encapsulation}}}} * 100\%$$

$${{{\rm{DLE}}}={{{\rm{mass}}}}；{{{\rm{of}}}\；{{{\rm{实际}}}}\；{{{\rm{药物}}}}\；{{{\rm{封装}}}/{{\rm{质量}}}}；\ \{{{\rm{of}}}\；{{{\ rm{理论}}}}\；{{{\rm{药物}}}}\；{{{\rm{封装}}}100%$$

(2)

(2)

In vitro drug release was investigated under specific conditions. Briefly, cRGD (Man)-pRNCThioether+DEA/R848 (each 0.5 mL) in PBS (pH 7.4, 10 mM, 150 mM NaCl) or acetate buffer (pH 5.0, 10 mM, 150 mM NaCl) in a dialysis bag (MWCO = 12000) was placed in 25 mL of media and were then placed in a shaking bed (37 oC, 200 rpm) (n = 3 independent experiments).

在特定条件下研究体外药物释放。简而言之，将PBS（pH 7.4,10mM，150mM NaCl）或乙酸盐缓冲液（pH 5.0,10mM，150mM NaCl）中的cRGD（Man）-PrNChiothere+DEA/R848（每种0.5mL）置于透析袋（MWCO 12000）中，然后置于摇床（37℃，200rpm）中（n=3个独立实验）。（笑声）。

At different time points (1, 2, 4, 6, 9, 12, and 24 h), 5 mL of the medium was removed and replaced with the same volume of fresh medium. Accumulation of R848 was detected using a fluorescence spectrophotometer.Targetability of cRGD-pRNCThioether+DEA in B16F10 cellsThe targetability of cRGD-pRNCThioether+DEA was investigated using flow cytometry and CLSM.

在不同的时间点（1,2,4,6,9,12和24小时），取出5mL培养基并用相同体积的新鲜培养基代替。使用荧光分光光度计检测R848的积累。cRGD-PrNC硫醚+DEA在B16F10细胞中的靶向性使用流式细胞术和CLSM研究cRGD-PrNC硫醚+DEA的靶向性。

For flow cytometry, B16F10 cells (5.0 × 105/well) were seeded into a six-well plate and cultured overnight, and this was followed by the addition of free FITC, cRGD-pRNCThioether+DEA@FITC, and pRNCThioether+DEA@FITC. After incubation for 10 or 30 min or for 1 h, the cells were subjected to trypsin digestion, centrifugation, suspension in PBS, and detection by flow cytometry.For CLSM characterization, B16F10 cells were seeded into 24-well plates containing cell slide cultures for 24 h.

为了进行流式细胞术，将B16F10细胞（5.0×105/孔）接种到六孔板中并培养过夜，然后加入游离FITC，cRGD-PrNC硫醚+DEA@FITC，和PRNC硫醚+DEA@FITC.孵育10或30分钟或1小时后，将细胞进行胰蛋白酶消化，离心，悬浮于PBS中，并通过流式细胞术检测。对于CLSM表征，将B16F10细胞接种到含有细胞载玻片培养物的24孔板中24小时。

Free FITC, cRGD-pRNCThioether+DEA@FITC, and pRNCThioether+DEA@FITC were added separately and incubated for 10 min, 30 min, and 1 h. After PBS washing (×3), cells were fixed for 15 min. After another PBS washing, cells were stained with DAPI (5 μg/mL, 10 min) and then sealed using coverslips onto microslides.

游离FITC，cRGD-PrNC硫醚+DEA@FITC，和PRNC硫醚+DEA@FITC分别加入并孵育10分钟，30分钟和1小时。PBS洗涤（×3）后，将细胞固定15分钟。再次PBS洗涤后，将细胞用DAPI（5μg/mL，10分钟）染色，然后用盖玻片密封在微玻片上。

After sealing with nail polish, images were captured using a CLSM.Targetability of Man-pRNCThioether+DEA in RAW264.7 cellsMan-pRNCThioether+DEA was also fabricated using a solvent-exchange method similar to that of cRGD-pRNCThioether+DEA and was characterized by DLS and.

用指甲油密封后，使用CLSM捕获图像。RAW264.7细胞中Man-PrnC硫醚+DEA的靶向性也使用类似于cRGD-PrnC硫醚+DEA的溶剂交换方法制造，并通过DLS和DLS表征。

B16F10 cells (1 × 106/ mouse) were inoculated subcutaneously into the right side of C57BL/6 mice to establish a melanoma mouse model. When the tumor volume reached approximately 100;mm3 by day 6, the mice were randomly divided into three groups that included PBS (G1), pRNCThioether+DEA@OVA (G2), and pRNCThioether+DEA@mRNA (G3) (n = 3 mice per group) (pRNCThioether+DEA: 5 mg/kg; OVA: 1 mg/kg; mRNA: 0.5 mg/kg).

将B16F10细胞（1×106/小鼠）皮下接种到C57BL/6小鼠的右侧以建立黑素瘤小鼠模型。当肿瘤体积达到约100时；mm3到第6天，将小鼠随机分为三组，包括PBS（G1），PRNC硫醚+DEA@OVA（G2）和PRNC硫醚+DEA@mRNA（G3）（每组n=3只小鼠）（PRNC硫醚+DEA:5mg/kg；OVA:1mg/kg；mRNA:0.5mg/kg）。

On days 7 and 14 after administration, peripheral blood mononuclear cells were extracted from mice for tetrameric analysis. T cells were extracted using a peripheral lymphocyte separation kit, stained with a CD3/CD8/Tetramer antibody, resuspended in PBS, and detected by flow cytometry.In vivo antitumor activity of cRGD- mix Man-pRNPThioether+DEA@R848C57BL/6 mice were injected with B16F10 cells (1 × 106/mouse) in the right flank to construct a melanoma tumor model.

在给药后第7天和第14天，从小鼠中提取外周血单核细胞用于四聚体分析。使用外周淋巴细胞分离试剂盒提取T细胞，用CD3/CD8/四聚体抗体染色，重悬于PBS中，并通过流式细胞术检测。cRGD-mix-Man-PrNP硫醚的体内抗肿瘤活性+DEA@R848C57BL/。

When the tumor grew to ~50 mm3, the mice were randomly divided into seven groups that included PBS (G1), Man-pRNCThioether+DEA (G2), cRGD-pRNCThioether+DEA (G3), cRGD- mix Man-pRNPThioether+DEA (G4), Man-pRNCThioether+DEA@R848 (G5), cRGD-pRNCThioether+DEA@R848 (G6), and cRGD-mix Man-pRNCThioether+DEA@R848 (G7) (cRGD-pRNPThioether+DEA: 1 mg/kg; Man-pRNPThioether+DEA: 0.5 mg/kg; R848: 0.1 mg/kg) (n = 5 mice per group).

当肿瘤生长至〜50 mm3时，将小鼠随机分为七组，包括PBS（G1），Man-PrnChiotheter+DEA（G2），cRGD-PrnChiotheter+DEA（G3），cRGD-mix-Man-PrnPhiotheter+DEA（G4），Man-PrnChiotheter+DEA@R848（G5），cRGD-PrNC硫醚+DEA@R848+DEA@R848（G7）（cRGD-PrNP硫醚+DEA:1mg/kg；Man-PrNP硫醚+DEA:0.5mg/kg；R848:0.1mg/kg）（每组n=5只小鼠）。

Different formulations were intravenously injected into tumor-bearing mice at 6, 9, and 12 days post-inoculation. Tumor length and width were measured using a Vernier caliper every two days, and the tumor volume curve was recorded. Body weight was recorded every two days. The therapeutic end point was when the tumor volume reached 2000 mm3 with normal organ (e.g., the heart, liver, spleen, lung, and kidneys) and tumor tissue extraction.

在接种后6,9和12天，将不同的制剂静脉注射到荷瘤小鼠中。每两天使用游标卡尺测量肿瘤长度和宽度，并记录肿瘤体积曲线。每两天记录一次体重。治疗终点是当肿瘤体积达到2000mm3时，正常器官（例如心脏，肝脏，脾脏，肺和肾脏）和肿瘤组织提取。

Partial tumor tissues were subjected to mechanical obstr.

对部分肿瘤组织进行机械观察。

Data availability

数据可用性

RNA-seq dataset is available in NCBI under accession codes PRJNA1126401. Figures/tables summarizing NMR are included in Supporting Information, and source data of NMR characterization of PEG-CPPA, PEG-PMMA, PEG-PMMA-PDEA, PPMA, PEG-PMMA-PPPMA, PEG-PMMA-P(PPMA-ME), PEG-PMMA-PPPMA, PEG-PMMA-P(PPMA-MPA), PEG-PMMA-P(PPMA-MPA- DEA), cRGD-PEG-PMMA-PPPMA and Man-PEG-PMMA-PPPMA are included in https://doi.org/10.6084/m9.figshare.26728720.

RNA-seq数据集可在NCBI中获得，登录号为PRJNA1126401。支持信息中包含总结NMR的数字/表格，以及PEG-CPPA，PEG-PMMA，PEG-PMMA-PDEA，PPMA，PEG-PMMA-PPPMA，PEG-PMMA-P（PPMA-ME），PEG-PMMA-PPPMA，PEG-PMMA-P（PPMA-MPA），PEG-PMMA-P（PPMA-MPA-DEA），cRGD-PEG-PMMA-PPPMA和Man-PEG-PMMA-PPPMA的NMR表征的源数据https://doi.org/10.6084/m9.figshare.26728720.

Source data for main and other Supplementary Figs. are provided with this paper and are available in the Figshare database at: https://doi.org/10.6084/m9.figshare.26094232. The data supporting the findings of this study are available within the article, Supplementary, or Source data files. Source data are provided with this paper..

本文提供了主要和其他补充图的源数据，可在Figshare数据库中获得：https://doi.org/10.6084/m9.figshare.26094232.支持本研究结果的数据可在文章，补充或源数据文件中找到。本文提供了源数据。。

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Download referencesAcknowledgementsThis research was supported by National Natural Science Foundation of China (52103191, 52103190 and 82073787), Start-up Grant (32340452 and 32340311) from Zhengzhou University, the NUS School of Medicine Dean’s Office (NUHSRO/2020/133/Startup/08, NUHSRO/2023/008/NUSMed/TCE/LOA, NUHSRO/2021/034/TRP/09/Nanomedicine, NUHSRO/2021/044/Kickstart/09/LOA, 23-0173-A0001), National Medical Research Council (MOH-001388-00, CG21APR1005, OFIRG23jul-0047), Singapore Ministry of Education (MOE-000387-00), and National Research Foundation (NRF-000352-00).Author informationAuthor notesThese authors contributed equally: Yichen Guo, Yongjuan Li.Authors and AffiliationsSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, ChinaYichen Guo, Mengzhe Zhang, Rong Ma, Yayun Wang, Xiao Weng, Jinjie Zhang, Zhenzhong Zhang & Weijing YangHenan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan Province, ChinaYichen Guo, Mengzhe Zhang, Rong Ma, Yayun Wang, Xiao Weng, Jinjie Zhang, Zhenzhong Zhang & Weijing YangThe Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, ChinaYongjuan LiDepartments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, SingaporeXiaoyuan ChenClinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeXiaoyuan ChenNanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeXiaoyua.

下载参考文献致谢本研究得到了国家自然科学基金（5210319152103190和82073787），郑州大学创业资助（32340452和32340311），国立大学医学院院长办公室（NUHSRO/2020/133/Startup/08，NUHSRO/2023/008/NUSMed/TCE/LOA，NUHSRO/2021/034/TRP/09/Nanomedicine，NUHSRO/2021/044/Kickstart/09/LOA，23-0173-A0001），国家医学研究委员会（MOH-001388-00，CG21APR1005，OFIRG23jul-0047），新加坡教育部（MOE-000387-00）和国家研究基金会（NRF-000352-00）。作者信息作者注意到，这些作者做出了同样的贡献：郭一晨，李永娟。作者和附属机构郑州大学药学院，郑州，郭一晨，张梦哲，马荣，王亚云，肖翁，张金杰，张振中和杨维京河南省郑州大学纳米医学靶向诊断与治疗重点实验室，郑州，河南省郑州，郭一晨，张梦哲，马荣，王亚云，王小翁，张金杰，张振中和杨维京郑州大学医学科学院感染与免疫中心，河南郑州，中国永娟新加坡国立大学林永禄医学院和设计与工程学院化学与生物分子工程与生物医学工程，新加坡陈晓源临床影像研究中心，林永禄医学院转化医学中心，新加坡国立大学新加坡国立大学陈晓元纳米医学转化研究项目，新加坡国立大学永禄林医学院，新加坡，新加坡小玉。

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PubMed Google ScholarContributionsW.Y., Z.Z., X.C., Y.G., and Y.L. conceived and designed the study. Y.G. and Y.L. performed the in vivo experiments. M. Z., R.M., Y.W., and X.W. performed the in vitro experiments. W.Y., Z.Z., X.C., Y.G. Y.L., and J.Z. contributed to the analysis and interpretation of the results and the writing of the manuscript.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献软件。Y、 。Y、 G.和Y.L.进行了体内实验。M、 Z.，R.M.，Y.W。和X.W.进行了体外实验。W、 Y.，Z.Z.，X.C.，Y.G.Y.L。和J.Z.为结果的分析和解释以及手稿的撰写做出了贡献。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleGuo, Y., Li, Y., Zhang, M. et al. Polymeric nanocarrier via metabolism regulation mediates immunogenic cell death with spatiotemporal orchestration for cancer immunotherapy.

转载和许可本文引用本文Guo，Y.，Li，Y.，Zhang，M。等人。通过代谢调节的聚合物纳米载体通过癌症免疫疗法的时空协调介导免疫原性细胞死亡。

Nat Commun 15, 8586 (2024). https://doi.org/10.1038/s41467-024-53010-0Download citationReceived: 24 October 2023Accepted: 22 September 2024Published: 04 October 2024DOI: https://doi.org/10.1038/s41467-024-53010-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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