Abstract The treatment of metastatic and drug-resistant tumors in the lungs and liver remains a major challenge for conventional chemotherapeutic agents, including doxorubicin. ML-016 is a novel injectable Phase I drug product developed by BrYet using a proprietary silicon “plateloid” technology designed to exploit distinct vascular and microenvironmental phenotypes. The platelet-shaped silicon microstructures (∼2.6 µm in diameter and ∼700 nm in thickness) are engineered to optimize hemodynamic behavior and endothelial interaction. The targeting mechanism of ML-016 integrates multiple phenotype-driven nodes acting sequentially across the tumor vasculature and microenvironment: enhanced margination under tumor-associated shear stress; preferential transmigration via polyglutamic acid-doxorubicin (pDox) conjugation; formation of pDox “exosomoids” and efficient internalization into tumor cells; local drug release through pH-mediated cleavage; and intracellular trafficking of released doxorubicin beyond the active range of multidrug-resistance pumps, yielding high perinuclear and nuclear accumulation. This multi-node phenotype targeting approach enhances tumor penetration, reduces systemic toxicity, and overcomes drug resistance. Our preclinical studies have shown strong antitumor efficacy in triple-negative breast cancer models with a 50% long-term functional cure (Nature Biotechnology, 2016, 34(4), 414-418). In a current lung metastasis model of soft-tissue sarcoma, ML-016 has produced durable tumor suppression and markedly prolonged survival, with 50-80% of treated animals surviving beyond five months after tumor inoculation, whereas all vehicle- or free-doxorubicin-treated animals succumbed within the same period. ML-016 has recently received Phase I/II Human Research Ethics Committee (HREC) approval in Australia, marking the initiation of first-in-human evaluation. Overall, ML-016 represents an innovative application of silicon plateloid technology that coordinates vascular, microenvironmental, and intracellular mechanisms to enable efficient phenotype-targeted therapy for resistant tumors in the lung and liver, supporting its continued development toward multi-cancer clinical validation. Citation Format: Qingxin Mu, Lorenzo Pradella, Brian Sapp, Mauro Ferrari. ML-016: A silicon “plateloid”-based phenotype targeting platform for lung and liver malignancies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 485.
Mu et al. (Fri,) studied this question.