Self-Decorating Albumin Nanoparticles as a Modular Drug Delivery Platform

Nanoparticles (NPs) offer significant advantages over conventional drug formulations, including enhanced bioavailability, reduced toxicity, and controlled release. Human serum albumin (HSA) is a biocompatible material widely used for NP fabrication, exemplified by Abraxane, an HSA-based NP formulation that improves chemotherapy delivery. Despite these benefits, HSA-NPs predominantly rely on passive tumor targeting through enhanced permeability and retention effect. Attempts to enhance active targeting via surface modifications often trigger immune responses, while scalable production remains limited by inconsistencies in size, drug loading, and stability. Here, we introduce a variant HSA (VA) as a building block for a novel nanocarrier, VA-NPs. Engineered with an α-helical domain that pairs with a complementary α-helical counterpart, VA enables VA-NPs to self-decorate their surface with diverse payload proteins through spontaneous and specific coiled-coil interactions. Unlike traditional approaches, this strategy eliminates the need for chemical conjugation or genetic fusion, establishing VA-NPs as a modular platform for multifunctional nanomedicines. This programmable protein display method offers a scalable and clinically relevant solution to current limitations in nanoparticle-based drug delivery, paving the way for next-generation nanomedicines with enhanced specificity, functional versatility, and therapeutic efficacy.