Iron Oxide Nanoparticles Enabled Ultrasound-Guided Theranostic Systems

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript "Iron Oxide Nanoparticles Enabled Ultrasound-Guided Theranostic Systems" focuses on the utilization of iron oxide nanoparticles (IONPs) to develop a new strategy for ultrasound-guided integrated diagnosis and treatment. It comprehensively reviews the principles, advantages, and challenges of multimodal technologies such as magnetoacoustic ultrasound and magnetic hyperthermia in tumor diagnosis and treatment, and provides systematic theoretical basis and technical outlooks to overcome the diagnostic and therapeutic difficulties caused by the tumor microenvironment. However, before this manuscript is considered for publication in "Magnetochemistry", several key issues need to be clarified and supplementary analyses conducted.

Comments and suggestions for authors

1. The conclusion section clearly points out the uniqueness of the multimodal integration mediated by IONPs (such as MMUS+PA+MH) compared to existing technologies.
2. In Section 2.1, the "MMUS-Swe" technology is mentioned, and in Section 4, the "MATA" method integrating this technology with magnetic resonance is proposed. These two methods overlap somewhat. It is recommended to further explain the differences between them.
3. In the "Conclusion" section of the 7th part, it is mentioned that "standardization, safety, and translation still present challenges", but it does not specifically explain how to solve these problems in clinical translation. It is recommended to add this information.
4. .To make the research background more comprehensive, please supplement the citation of the latest literature. For example, It is recommended that the author add a discussion on biological safety and refer to DOI:10.1021/acsnano.5c01399; It is recommended to refer to DOI: 10.1021/acsnano.5c04774 to explain that the purpose of the integrated diagnosis and treatment technology. 

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Peer Review of the Manuscript

“Iron Oxide Nanoparticles Enabled Ultrasound-Guided Theranostic Systems” by the authors Thiago Tiburcio Vicente , Prabu Periyathambi , Ariane Franson Sanches , Marina Yuki Azevedo Nakakubo , Nicholas Zufelato , Karina Bezerra Salomão , María Sol Brassesco , Theo Zeferino Pavan , Koiti Araki , Antônio A. O. Carneiro

This review addresses a highly relevant and intellectually compelling topic: the integration of iron oxide nanoparticles (IONPs), particularly superparamagnetic iron oxide nanoparticles (SPIONs), into ultrasound-guided theranostic platforms for cancer diagnosis and therapy. The focus on magnetomotive ultrasound (MMUS) and its combination with magnetic hyperthermia (MH) and photoacoustic (PA) imaging is timely, as these approaches promise lower cost, real-time monitoring, minimal invasiveness, and compatibility with clinical settings—especially in resource-limited environments. The manuscript is generally well-structured and provides a comprehensive overview of current developments. However, several improvements would significantly enhance its scientific rigor, clarity, and utility to the research community.

Major Comments:

1. While the introduction effectively describes the multifunctionality of iron oxide nanoparticles (IONPs), it omits one of their most important advantages: low systemic toxicity and biodegradability. This is the primary reason why iron oxide-based nanomaterials—as opposed to other magnetic alternatives such as cobalt or nickel ferrites—are clinically preferred and FDA-approved. The authors should explicitly emphasize this point at the beginning of the introduction to justify the central role of IONPs in theranostics.
2. The transition from general IONP applications to MMUS/PA is abrupt. The final paragraph of the Introduction (lines 178–182) should be expanded to clearly articulate why ultrasound-guided methods deserve dedicated attention: their real-time capability, absence of ionizing radiation, portability, cost-effectiveness, and potential for point-of-care use. A stronger rationale will help position this review as filling a specific gap in the literature, where most IONP reviews emphasize MRI or MPI but neglect emerging acoustic techniques.
3. Figure 1 is conceptually confusing. Two MRI icons suggest two different modalities, but it is unclear which they are and which particle types correspond to which. Visual consistency and labeling need to be improved to avoid misinterpretation.
4. Introduction Structure. The current division—Introduction followed by an unlabeled subsection and then “1.1. Overview of IONPs”—is awkward. It would be clearer to split the Introduction into two logical parts or eliminate the “1.1” heading .
5. The review frequently mentions both IONPs and SPIONs (particle size smaller than the magnetic domain), but does not critically address how particle size and magnetic properties (ferromagnetic, superparamagnetic) influence MMUS performance. The authors should discuss whether particle size, crystallinity, or coating influence displacement amplitude, signal-to-noise ratio, or depth sensitivity. Even if the literature is sparse, acknowledging this gap in the Conclusions would strengthen the review. If possible, the influence of particle size should be addressed elsewhere in the review.
6. To facilitate reader navigation through the extensive cited literature, authors should include a summary table listing key studies using IONPs for MMUS, PA, including in combination with other methods. The table should include: composition, size, shape of iron oxide nanoparticles, surface coating, magnetic properties, and key findings.

Minor Comments

• Reference Quality: While many cited references are high-quality reviews (e.g., refs 43–45), the manuscript would benefit from inclusion of seminal original research articles that first demonstrated key concepts. 

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Review Article: “Iron Oxide Nanoparticles Enabled Ultrasound-Guided Theranostic Systems”

This review summarizes the current state of IONP-based contrast agents. The review is highly focused and well structured. The review is well written, has high-quality images, and should attract the reader's attention. However, there are a few remarks/suggestions:

1. The introduction requires greater emphasis on iron oxide nanoparticles, as they are one of the main topics of this review. It would be beneficial to add a paragraph specifically discussing iron oxide nanoparticles, particularly their properties. Additionally, incorporating some recent literature could enhance the introduction.

2. More images should be included to improve the visualization of the text.
3. More literature of the last 5 years could be overviewed.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Accept

Reviewer 2 Report

Comments and Suggestions for Authors

Peer Review Round 2 of the Manuscript “Iron Oxide Nanoparticles Enabled Ultrasound-Guided Theranostic Systems” by Thiago Tiburcio Vicente et al.

The revised manuscript effectively addresses the majority of the concerns raised in the initial review, enhancing its overall clarity, scientific depth, and utility. The authors

• Clarified the rationale for using iron oxide nanoparticles by emphasizing their low toxicity and biodegradability;
• Revised Figure 1 for improved clarity and conceptual consistency;
• Changed the introduction structure by removing the confusing “1.1” subsection;
• Discussed the influence of particle size and magnetic properties (superparamagnetic vs. ferromagnetic) on MMUS performance;
• Added a comprehensive summary table (Table 1) that effectively organizes key studies by nanoparticle characteristics and applications.

The transition to the specific ultrasound-guided methods (MMUS and PA) remains somewhat abrupt in places, with the final paragraphs of the introduction focusing more on general IONP advantages and less on explicitly justifying the dedicated focus on these emerging, low-cost, real-time, non-ionizing modalities as a distinct literature gap. However, this is now a relatively minor issue given the overall improvements in rationale and contextualization throughout the text. Overall, the revised manuscript is now well-structured, scientifically rigorous, timely, and fills an important niche in reviewing ultrasound-integrated IONP theranostics — an area underrepresented compared to MRI/MPI-focused reviews.