PINCLUS · Chaotropic transmembrane delivery of proteins

Protein biologics hold immense therapeutic promise, yet their clinical potential is constrained by a fundamental barrier: the cellular membrane. While several protein-based drugs have achieved clinical success, they remain limited to extracellular targets. Unlocking intracellular access would dramatically expand the therapeutic scope of protein drugs, enabling intervention at previously inaccessible disease sites.Current intracellular delivery strategies rely on physical or amphiphilic mechanisms, both of which suffer from critical drawbacks including cytotoxicity, cargo aggregation, and endosomal entrapment. PINCLUS proposes a transformative alternative by leveraging super-chaotropic boron clusters as transmembrane carriers. These inorganic, doubly anionic, water-soluble clusters bypass endosomal pathways and avoid aggregation or membrane disruption, offering a biocompatible route for intracellular transport.Building on pioneering work in chaotropic delivery, PINCLUS introduces a novel strategy using boron clusters as protein nanocarriers to enable precise modification across diverse protein types and ensures traceless release of the native protein upon internalization, preserving biological function.Through interdisciplinary training in chemistry, biology, and biophysics, and supported by the host’s expertise in chaotropic transporters, this action will establish the first proof-of-concept for selective intracellular delivery of chaotropic protein hybrids. PINCLUS will unlock new frontiers in protein drug development and empower the applicant’s transition to scientific independence.