Hyperbranched Self-Immolative Polymers (<i>h</i>SIPs) for Programmed Payload Delivery and Ultrasensitive Detection

Abstract

Upon stimuli-triggered single cleavage of capping moieties at the focal point and chain terminal, self-immolative dendrimers (SIDs) and linear self-immolative polymers (<i>l-</i>SIPs) undergo spontaneous domino-like radial fragmentation and cascade head-to-tail depolymerization, respectively. The nature of response selectivity and signal amplification has rendered them a unique type of stimuli-responsive materials. Moreover, novel design principles are required for further advancement in the field of self-immolative polymers (SIPs). Herein, we report the facile fabrication of water-dispersible SIPs with a new chain topology, hyperbranched self-immolative polymers (<i>h</i>SIPs), by utilizing one-pot AB₂ polycondensation methodology and sequential postfunctionalization. The modular engineering of three categories of branching scaffolds, three types of stimuli-cleavable capping moieties at the focal point, and seven different types of peripheral functional groups and polymeric building blocks affords both structurally and functionally diverse <i>h</i>SIPs with chemically tunable amplified-release features. On the basis of the <i>h</i>SIP platform, we explored myriad functions including visible light-triggered intracellular release of peripheral conjugated drugs in a targeted and spatiotemporally controlled fashion, intracellular delivery and cytoplasmic reductive milieu-triggered plasmid DNA release via on/off multivalency switching, mitochondria-targeted fluorescent sensing of H₂O₂ with a detection limit down to ∼20 nM, and colorimetric H₂O₂ assay via triggered dispersion of gold nanoparticle aggregates. To further demonstrate the potency and generality of the <i>h</i>SIP platform, we further configure it into biosensor design for the ultrasensitive detection of pathologically relevant antigens (e.g., human carcinoembryonic antigen) by integrating with enzyme-mediated cycle amplification with positive feedback and enzyme-linked immunosorbent assay (ELISA)