Blocked bioorthogonal chemistry enabled switchable bioorthosome to improve liposomal drug delivery for glioblastoma therapy

Glioblastoma (GBM) interventions necessitate exceptional precision due to the presence of blood-brain barrier (BBB) and its intricate co-growth with neuron and glial cells. Here, we developed a blocked bioorthogonal chemistry enabled liposome, termed Bioorthosome, with switchable BBB-crossing ligand that could block the bioorthogonal moieties in normal tissue and blood circulation. Upon traversing the BBB and reaching tumor region, the BBB-crossing ligand could detach from the Bioorthosome under acidic tumor microenvironment and switch to the bioorthogonal moieties to react with the metabolically expressed azide-containing sialylations on GBM cell surface. This switchable bioorthogonal chemistry ensures that only GBM cells are targeted, thereby enhancing the precision of liposomal drug delivery. In vitro and in vivo studies have demonstrated that the Bioorthosome efficiently crosses the BBB and undergoes a ligand-switching process to selectively recognize GBM cells while sparing normal brain tissue, leading to enhanced therapeutic efficacy and reduced off-target accumulation. By integrating bioorthogonal reactions with a tumor microenvironment-responsive ligand-switching mechanism, our Bioorthosome design overcomes the limitations of inefficient BBB permeability and suboptimal anti-GBM drug delivery, paving the way for more precise GBM-targeted therapies and the advancement of more effective treatment strategies.