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Volume 116
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Modularly assembled nanocomposites with dual TME-responsiveness and multi-targeting for selective drug delivery in ovarian cancer therapy
Shanmei Yin a, Ruixin Gong a, Ying Liao a, Bowen Yang b c, Zongning Yin a *
a Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
b Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
c Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China
10.1016/j.partic.2026.06.026
Volume 116, September 2026, Pages 297-310
Received 13 March 2026, Revised 29 May 2026, Accepted 22 June 2026, Available online 30 June 2026, Version of Record 11 July 2026.
E-mail: zongningyin@163.com
Highlights

• Hemoglobin (Hb) serves as both a CD163 ligand and a GSH-responsive switch for M2 TAM targeting.

• Modular assembly promises flexible drug ratios to combat tumor heterogeneity.

• TME-responsive multi-biomaterial design enables rapid, precise tumor accumulation.

• Surface modulation enables controlled dual-drug delivery.

• Simvastatin repolarizes M2 TAMs to enhance DOX efficacy.


Abstract

Conventional drug delivery systems for ovarian cancer are hindered by the tumor microenvironment (TME), characterized by high interstitial pressure and M2 tumor-associated macrophages (TAMs), leading to off-target effects, immunosuppression, and carrier-related systemic toxicity. To overcome these limitations, we developed BHS/HT-PSD nanocomposites (BHS/HT-PSD NCs) with favorable biocompatibility, TME responsiveness, and targeting ability. BHS/HT-PSD NCs were assembled via electrostatic adsorption from two constituent modules: BHS nanoparticles employing hemoglobin (Hb) as a core functional carrier for simvastatin loading, and HT-PSD micelles modified with hyaluronic acid and TNYL peptide for doxorubicin delivery. With negative charge and high loading capacity, BHS/HT-PSD NCs achieved precise targeting of M2 TAMs and tumor cells through Hb and TNYL peptide, respectively. Glutathione and hyaluronidase in the TME triggered NCs’ disintegration and drug release, thereby improving drug penetration into tumors. In tumor-bearing mice, BHS/HT-PSD NCs rapidly accumulated at tumor sites, achieving 5.3-fold higher drug accumulation within 2 h. The treatment also induced M2 TAM repolarization and achieved a tumor inhibition rate of 70.7%, while maintaining excellent safety. This study presents a novel strategy for high-efficiency and low-toxicity ovarian cancer therapy, leveraging TME-responsive functional constituents within BHS/HT-PSD NCs that act as smart switches to precisely synergize immune regulation with chemotherapy.

Graphical abstract
Keywords
Nanocomposite; Dual-stimuli responsive; Modular assembly; Hemoglobin; Ovarian cancer
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