Dual-template molecular imprinting enables fully synthetic phosphatidylserine-targeted cancer therapy.

Authors

Shuhan Hu, Wenjing Yu, Luxi Chen, Muhammad Mujahid Ali, Juntao Zhou, Lei Ye, Lianghai Hu

Published in

Nanoscale. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Phosphatidylserine (PS) exposed on tumor cell membranes is an attractive target for cancer therapy, but current PS-targeting strategies depend largely on biologically derived ligands that suffer from calcium dependence, limited stability, immunogenicity risk, and manufacturing complexity. Here, we report a fully synthetic therapeutic platform based on dual-template molecular imprinting that integrates PS-targeted tumor recognition with pH-responsive doxorubicin (Dox) delivery in a single nanocarrier. By co-imprinting the PS polar head group and Dox, the resulting molecularly imprinted polymer nanoparticles (dt-MIP) generate orthogonal binding sites for membrane targeting and drug loading, achieving high binding capacities for PS and Dox (Q_max ∼ 180 mg g^-1 and ∼37 mg g^-1, respectively), high selectivity, minimal drug leakage at physiological pH, and accelerated release in acidic environments. The dt-MIP recognized surface-exposed PS with specificity comparable to Annexin V and enabled PS-dependent Dox delivery across multiple cell lines, with delivery efficiency correlating with the degree of PS externalization. In triple-negative breast cancer cells, Dox-loaded dt-MIP markedly enhanced intracellular drug accumulation and reduced cell viability to ∼8% at 200 μg mL^-1 dt-MIP, compared with ∼70% for free Dox at the same dose. In an MDA-MB-231 xenograft model, dt-MIP achieved tumor-selective accumulation and substantially suppressed tumor growth while maintaining a favorable safety profile. These results establish dual-template molecular imprinting as a general strategy for constructing fully synthetic, target-directed cancer therapeutics, positioning PS-imprinted nanocarriers as an alternative to biologically derived targeting systems.

PMID:
42885584
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.

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