In this project, we developed an advanced “Golden-ADC” nanoplatform that merges the selectivity of antibody-drug conjugates (ADCs) with the versatility and stability of nanoparticle-technology. The platform was functionalized with antibodies recognizing Trop-2, a clinically validated marker expressed in many TNBC tumors, and with chemotherapeutic payloads commonly used in FDA-approved ADCs. Using a simple and robust conjugation strategy, both antibodies and drugs were stably anchored onto the nanoparticle surface, overcoming the complex design and stability limitations that restrict current ADC technologies. We systematically evaluated the platform’s efficacy and safety in vitro and in vivo. In human TNBC cells, drug-linked nanoparticles demonstrated potent cytotoxicity, and importantly, dual-drug conjugation on a single nanoparticle produced synergistic tumor-cell killing. Mechanistic studies revealed that the drugs were selectively released in the lysosomes of cancer cells, mirroring the intracellular activation process of clinical ADCs but with enhanced control and efficiency. In TNBC tumor-bearing mice, insulin-coated Golden-ADCs achieved deep intratumoral penetration and uniform dissemination, as shown by advanced imaging and quantitative biodistribution analyses. Treatment with the insulin-guided nanoplatform led to marked tumor growth inhibition, with the most pronounced effect observed when both chemotherapies were co-delivered. Remarkably, tumor suppression was achieved in both high- and low-Trop-2–expressing tumors, demonstrating broad applicability beyond antigen-rich cancers. While free drug formulations induced severe toxicity and early mortality, Golden-ADC treatment was well tolerated, with no observable systemic toxicity. Biodistribution studies confirmed minimal cardiac accumulation, addressing a key limitation of conventional ADCs and chemotherapies known for cardiotoxic side effects. Together, these results establish the Golden-ADC nanoplatform as a safe, potent, and broadly applicable next-generation ADC alternative, offering scalable chemistry, multi-payload flexibility, and improved therapeutic precision. Based on these breakthrough preclinical findings, a provisional patent has been filed, and a scientific manuscript is currently in preparation for publication.
