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Although conventional treatments including surgery, chemotherapy, and radiotherapy are effective, they are confronted with challenges such as tumor heterogeneity, systemic toxicity, and recurrence driven by drug resistance. To overcome these limitations, natural products have emerged as promising therapeutic alternatives owing to their multi-target efficacy and favorable biocompatibility. However, their clinical translation is still hindered by poor chemical stability, low aqueous solubility, and inadequate bioavailability. Nanodelivery systems offer a transformative solution by enhancing bioavailability and enabling precision targeting through the enhanced permeation and retention effect, thereby widening the therapeutic window and minimizing off-target toxicity. Purpose: This review evaluates diverse nanoparticle-based delivery systems and their targeting mechanisms in natural product-based breast cancer therapy. By examining inherent advantages and translational challenges, this analysis provides critical insights into the clinical development and application of these nanoformulations. Methods: A systematic literature search was performed in PubMed, ScienceDirect, Springer, Taylor &amp; Francis, and Web of Science to identify relevant studies on natural product-based nanoformulations for breast cancer therapy. Results: Natural products exert anti-breast cancer effects through mechanisms such as inducing apoptosis, arresting the cell cycle, inhibiting invasion and metastasis, suppressing angiogenesis, and regulating autophagy. To overcome clinical hurdles, three complementary targeting strategies have been developed: passive, active, and stimuli-responsive targeting. These advances are shifting nanomedicines toward active precision therapy, markedly improving the therapeutic index. With multiple formulations already approved or in clinical pipelines, this field is rapidly progressing from laboratory research to clinical implementation. Conclusions: Natural products possess potent anti-breast cancer effects, and the application of nanodelivery technology effectively overcomes their inherent limitations of poor stability and low bioavailability. Although preliminary findings are promising, large-scale, randomized controlled clinical trials are urgently needed to systematically evaluate their safety, efficacy, and practical potential for clinical translation in breast cancer management.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091101","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:08:43Z","timestamp":1788275323000},"page":"1101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Product-Based Nanomedicine in the Treatment of Breast Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5972-166X","authenticated-orcid":false,"given":"Kaiyan","family":"Su","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9749-717X","authenticated-orcid":false,"given":"Yuxuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0279-8784","authenticated-orcid":false,"given":"Quanjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shanghai Sixth People\u2019s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103851","DOI":"10.1016\/j.breast.2024.103851","article-title":"Inequality in breast cancer: Global statistics from 2022 to 2050","volume":"79","author":"Liao","year":"2025","journal-title":"Breast"},{"key":"ref_2","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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