Researchers develop organoids for secretion of anticancer drug

Organoids are three-dimensional cellular constructs generated in vitro from adult stem cells, pluripotent stem cells, or tissue progenitor cells. They recapitulate key structural and functional features of native organs and are widely used in disease modeling, drug screening, and regenerative medicine.

On April 17, 2026, a research team led by Professors GU Zhen and YU Jicheng from the School of Pharmacy at Zhejiang University, the Jinhua Institute, and the State Key Laboratory of Advanced Drug Delivery and Release Systems, in collaboration with Professor WANG Shenqiang from Soochow University and Professor HU Huili from Shandong University, published a study in Nature Biomedical Engineering entitled "Mammary organoid-based depot for post-surgical chemotherapy and gland regeneration." The study reports an organoid-based drug delivery platform inspired by the physiological process of lactation. In this system, mammary organoids function as both "living drug depots" and "regenerative units", enabling sustained release of anticancer agents through a lactation-mimicking mechanism, thereby suppressing postoperative tumor recurrence while promoting mammary gland regeneration (Fig.1).

Fig.1 Schematic illustration of the construction of engineered mammary organoids and their application in post-surgical chemotherapy and mammary gland regeneration.

A new paradigm: Organoids as both drug reservoirs and regenerative seeds

Breast cancer remains one of the most prevalent malignancies among women. Although surgical resection removes the majority of tumor tissue, residual microscopic lesions often lead to recurrence. Moreover, surgery can damage mammary tissue, impair lactation function, and impose significant psychological burdens on patients.

To address these challenges, the researchers adopted an unconventional strategy by directly utilizing engineered mammary organoids as "living drug reservoirs" and "regenerative units". Mammary organoids are three-dimensional miniaturized models of the mammary gland, comprising intact myoepithelial and luminal layers and possessing intrinsic secretory and contractile capabilities (Fig.2a). By inducing a lactation-like state, the organoids accumulate abundant lipid droplets, which serve as natural reservoirs for drug loading. The team designed a pH-sensitive prodrug composed of all-trans retinal (ATRA) and doxorubicin (DOX). Due to its lipophilic nature, the prodrug can be efficiently encapsulated within lipid droplets of lactating organoids, thereby enhancing drug-loading efficiency while minimizing premature toxicity. Importantly, after implantation, myoepithelial cells within the organoids undergo autonomous contraction, mimicking lactation to release drug-loaded lipid droplets into the tumor microenvironment, enabling controlled and sustained drug delivery (Fig.2b).

Fig.2 Construction of the engineered mammary organoid-based drug depot. (a) Microscopic images of mammary organoids at different time points during culture. Scale bar: 200 μm. (b) Immunofluorescence staining of engineered mammary organoids, showing milk proteins (green) and luminal epithelial cells (red). Scale bar: 50 μm.

Dual advantages: Effective tumor suppression and functional regeneration

Following implantation into the post-surgical cavity in mice, the engineered organoids exhibited rhythmic contraction of myoepithelial cells, leading to the "secretion" of drug-loaded lipid droplets into surrounding tissues. Upon reaching the acidic tumor microenvironment, the prodrug undergoes cleavage, releasing active doxorubicin and ATRA to selectively eliminate residual tumor cells. ATRA further inhibits cancer stemness and helps overcome drug resistance. In a mouse model of breast cancer recurrence, the treatment reduced recurrence rates to 25%, with 75% of mice surviving beyond 100 days. Unlike conventional scaffold materials, organoids act as "living implants" that not only deliver therapeutics but also spontaneously integrate with host mammary tissue, reconstructing ductal architecture. Remarkably, the regenerated mammary tissue restored lactation function following pregnancy.

The researchers also demonstrated the translational potential of this strategy. Using human induced pluripotent stem cells (iPSCs), they successfully generated human-derived mammary organoids capable of efficient prodrug loading and lactation-like drug release. In humanized mouse models of breast cancer, these organoids suppressed tumor recurrence and promoted regeneration of human mammary tissue.

The team is currently exploring the extension of this "organoid-based drug delivery" platform to other tumor types and corresponding tissue regeneration. In the future, integration with patient-derived stem cells may enable personalized precision therapy and tissue reconstruction.

Source: School of Pharmacy
Editor: HAN Xiao