Reviewer: 1
评论者： 1
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> Recommendation: Publish after minor revisions noted.
> 建议：在记录到次要修订后发布。
>
> Comments:
> 评论：
> The manuscript titled “Enhanced Antibiotic Delivery Platform Functionalized with Nutrient Restriction and Combination Therapy Against Bacterial Infections” by Xu et al. presents an innovative and highly promising approach to developing a multifunctional drug delivery system. This system enhances antibiotic efficacy by restricting bacterial access to essential nutrients and utilizing a combination of antibiotics to achieve synergistic bactericidal effects. Polydopamine (PDA) is employed to chelate iron ions, effectively inhibiting bacterial growth, while rifampicin and polymyxin B, released from PLGA microspheres, disrupt the bacterial membrane, leading to a significant acceleration of bacterial death. This study introduces valuable strategies for combating multidrug-resistant (MDR) bacteria, and the novel integration of nutrient limitation within the delivery platform is particularly noteworthy. However, several areas of the manuscript require minor revisions:
> Xu 等人题为“增强型抗生素递送平台功能化，营养限制和针对细菌感染的联合疗法”的手稿提出了一种创新且极具前景的开发多功能药物递送系统的方法。该系统通过限制细菌获得必需营养素并利用抗生素组合来实现协同杀菌效果，从而提高抗生素疗效。聚多巴胺 （PDA） 用于螯合铁离子，有效抑制细菌生长，而 PLGA 微球释放的利福平和多粘菌素 B 破坏细菌膜，导致细菌死亡显着加速。本研究介绍了对抗多重耐药 （MDR） 细菌的宝贵策略，其中营养限制在递送平台中的新颖整合尤其值得注意。但是，手稿的几个方面需要稍作修改：
>
> 1. There are multiple formatting issues related to punctuation. For example, in Section 2.4: "PDA (4 mg/ml), PEG-PDA@PLGA (200 μg/ml), Rif (160 μg/ml)"; in Section 2.14: "OD600 = 0.5"; in Section 2.17: "(weight 20.0 ± 0.5 g)"; and in Section 2.19: "means ± SD." These inconsistencies should be corrected for a more polished presentation.
> 1.存在 多个与标点符号相关的格式问题。例如，在第 2.4 节中：“PDA （4 mg/ml）、PEG-PDA@PLGA （200 μg/ml）、Rif （160 μg/ml）”;在第 2.14 节中：“OD600 = 0.5”;在第 2.17 节中：“（重量 20.0 ± 0.5 克）”;在第 2.19 节中：“指 ± SD”。这些不一致之处应该得到纠正，以获得更精美的演示文稿。
> 2. The thickness of the horizontal lines in Figures 5 and 6 is inconsistent. Please standardize the formatting of these figures for uniformity.
> 2.图 5 和图 6 中水平线的粗细不一致。请标准化这些图表的格式以保持统一。
> 3. In Section 2.5, the full term "polydopamine" is used instead of its abbreviated form (PDA), which was introduced earlier in the text. Please ensure consistency in terminology throughout the manuscript.
> 3.在第 2.5 节中，使用了完整的术语 “polydopamine” 而不是文中前面介绍的缩写形式 （PDA）。请确保整个手稿中的术语一致。
> 4. While the manuscript presents a series of characterization results, it is not immediately clear how these results compare with previous studies. A comparative analysis would help to highlight the scientific advances of this research. Additionally, more references should be included to further contextualize and support the findings.
> 4.虽然手稿提出了一系列表征结果，但目前尚不清楚这些结果与以前的研究相比如何。比较分析将有助于突出这项研究的科学进展。此外，应包括更多参考资料，以进一步背景化和支持这些发现。
> 5. Proofread the manuscript to correct any grammatical errors and improve the use of the English language.
> 5.校对手稿以纠正任何语法错误并改进英语的使用。
Reviewer: 2
审稿人：2
>
> Recommendation: Major revisions needed as noted.
> 建议：如前所述，需要进行重大修订。
>
> Comments:
> 评论：
> This research article reported the porous poly (lactic-co-glycolic acid)-cored structure with rifampicin encapsulated and then further coated with polydopamine and iron ions. This materials showed good efficiencies in intestinal infection model in mice.
> 本研究文章报道了多孔聚（乳酸-羟基乙酸共聚物）-有芯结构，利福平被包埋，然后进一步涂有聚多巴胺和铁离子。 该材料在小鼠肠道感染模型中显示出良好的效率。
> 1. Figure 2H described the “in vitro” RIF drug release, however, no cells or biological models were used and reported in session 2.8 experimental for this study. Session 2.8 should also report how to attain different pH solutions. If there are cells or biological models used, were they stable for the experiments at such pH values?
> 1.图 2H 描述了“体外”RIF 药物释放，但是，在本研究的 2.8 会话实验中没有使用和报告细胞或生物模型。第 2.8 节还应报告如何获得不同的 pH 值溶液。如果使用了细胞或生物模型，它们在这样的 pH 值下对实验是否稳定？
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> 2. In the same RIF release experiments (Figure 2H), release amount (%) should be reported besides the release rate (%). For reporting the release rate, a proper unit in terms of per minute or per hour should be reported.
> 2.在相同的 RIF 释放实验中（图 2H），除了释放速率 （%） 外，还应报告释放量 （%）。要报告释放速率，应报告每分钟或每小时的适当单位。
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> 3. What was the mechanism for the RIF drug (MW=822) release from the particle? Were the PDA@PLGA degraded and both PDA and PLGA breaking into pieces? More characterization data and discussion will be needed to elucidate the mechanism of drug release.
> 3.RIF 药物 （MW=822） 从颗粒中释放的机制是什么？PDA@PLGA是否降解，PDA 和 PLGA 都碎裂了？需要更多的表征数据和讨论来阐明药物释放的机制。
> 4. Pore sizes and pore volumes of the Rif-PLGA, PDA@PLGA and PEG-PDA@PLGA particles should be provided.
> 4.应提供 Rif-PLGA、PDA@PLGA 和 PEG-PDA@PLGA 颗粒的孔径和孔径体积。
> 5. The conclusion part needs to be more specific to what had been discovered.
> 5.结论部分需要更具体地说明所发现的内容。
> 6. The references part is generally not very up-to-date. There are recent examples of using rifampicin-loaded nanoparticles for antifungal and anti-bacterial purposes.
> 6.参考部分通常不是很最新。最近有使用负载利福平的纳米颗粒用于抗真菌和抗菌目的的例子。
Reviewer: 3
审稿人： 3
>
> Recommendation: Major revisions needed as noted.
> 建议：如前所述，需要进行重大修订。
>
> Comments:
> 评论：
> This article explores the antibacterial efficacy of PEG-PDA@PLGA microspheres, designed to target nutrient competition through iron chelation, aiming to curb the growth of antibiotic-resistant bacteria. By incorporating the dual mechanisms of drug release and Fe³⁺ chelation, the study presents promising data supporting the enhanced bactericidal efficacy of this system, attributed to PDA’s capacity to both interfere with bacterial iron metabolism and synergize with antibiotics. This approach provides a potential avenue for targeting pathogenic mechanisms more precisely, potentially minimizing host cell impact. The manuscript is well-constructed and supported by comprehensive experimental data; however, it would benefit from addressing the following points to strengthen the clarity and relevance of the work.
> 本文探讨了 PEG-PDA@PLGA 微球的抗菌功效，旨在通过铁螯合来靶向营养竞争，旨在抑制抗生素耐药细菌的生长。通过结合药物释放和 Fe³⁺ 螯合的双重机制，该研究提供了有希望的数据，支持该系统增强的杀菌功效，这归因于 PDA 既能干扰细菌铁代谢又能与抗生素协同作用。这种方法为更精确地靶向致病机制提供了一种潜在的途径，从而可能最大限度地减少对宿主细胞的影响。手稿结构合理，并有全面的实验数据支持;但是，解决以下几点以加强工作的清晰度和相关性将受益。
> 1. The current introduction lacks an emphasis on innovation, focusing mainly on background and the status quo without showcasing the uniqueness and advantages of this study. It is recommended to highlight the core innovation points of PEG-PDA@PLGA material, such as the dual-action mechanism (combining antibacterial drug release and iron chelation), environmental responsiveness, and its potential in combating antibiotic-resistant bacterial infections. Additionally, referring to unresolved challenges or unmet clinical needs that this study addresses would enhance its innovation and practical relevance.
> 1.目前的引言缺乏对创新的强调，主要关注背景和现状，而没有展示这项研究的独特性和优势。建议强调 PEG-PDA@PLGA 材料的核心创新点，例如双重作用机制（结合抗菌药物释放和铁螯合）、环境响应性及其在对抗抗生素耐药细菌感染方面的潜力。此外，提及本研究解决的未解决的挑战或未满足的临床需求将增强其创新和实际相关性。
> 2. The introduction mentions a strategy of inhibiting pathogen growth through nutrient competition, discussing key nutrients such as iron, amino acids, and B vitamins. However, the subsequent design focuses only on iron chelation for nutrient competition. Why was iron prioritized over other nutrients (such as amino acids or B vitamins)? Are there supporting experiments or literature indicating a particular advantage of iron chelation against resistant strains?
> 2.引言提到了一种通过营养竞争抑制病原体生长的策略，讨论了铁、氨基酸和 B 族维生素等关键营养素。然而，随后的设计仅侧重于营养竞争的铁螯合。为什么铁优先于其他营养素（如氨基酸或 B 族维生素）？是否有支持实验或文献表明铁螯合对耐药菌株具有特殊优势？
> 3. Regarding the antibacterial effects of the PDA-Fe³⁺ chelation mechanism, how is Fe³⁺ controlled and stabilized after chelation? Could this lead to other biological effects (e.g., inhibition of host cell iron metabolism)?
> 3.关于 PDA-Fe³⁺ 螯合机制的抗菌作用，螯合后如何控制和稳定 Fe³⁺？这是否会导致其他生物学效应（例如，抑制宿主细胞铁代谢）？
> 4. Fig. S1 (A) shows scanning electron micrographs of PLGA microspheres prepared with different masses of BSA (20, 40, 60 mg), but the figure labels indicate 40, 60, and 80 mg. The experimental section also mentions the addition of 20 mg of BSA and 0.05% ammonium bicarbonate in the pore-forming mixture without explaining these choices.
> 4.图 S1 （A） 显示了用不同质量的 BSA（20、40、60 毫克）制备的 PLGA 微球的扫描电子显微照片，但图标指示为 40、60 和 80 毫克。实验部分还提到在成孔混合物中添加了 20 mg BSA 和 0.05% 碳酸氢铵，但没有解释这些选择。
> 5. In Section 3.3, it mentions “we screened various drug combinations and identified Rif and PB as a synergistic pair,” but only the Rif and PB combination is shown. What about the other drug combinations?
> 5.在第 3.3 节中，它提到“我们筛选了各种药物组合，并将 Rif 和 PB 确定为协同对”，但只显示了 Rif 和 PB 组合。其他药物组合呢？
> 6. In Section 3.3, the figures for reactive oxygen species (ROS) determination and ATP determination results do not match the labels provided in the article.
> 6.在第 3.3 节中，活性氧 （ROS） 测定和 ATP 测定结果的数字与文章中提供的标签不匹配。
> 7. Section 3.4 refers to blood compatibility results in Fig. S6, which are not displayed in the Supplementary Materials.
> 7.第 3.4 节引用了图 1 中的血液相容性结果S6，这些内容未显示在补充材料中。
> 8. Detailed descriptions of the experimental process improve reproducibility, but the extensive length may affect readability and dilute the core contributions of the paper. It is recommended to move the basic experimental descriptions to the supplementary materials, focusing on key innovative experiments and data analysis in the main text.
> 8.实验过程的详细描述提高了可重复性，但冗长的长度可能会影响可读性并稀释论文的核心贡献。建议将基础实验描述移至补充材料中，重点放在正文中的关键创新实验和数据分析上。