Super-small zwitterionic micelles enable the improvement of blood-brain barrier crossing for efficient orthotopic glioblastoma combinational therapy

Glioblastoma multiforme (GBM) remains incurable in clinical, nanotechnology-based drug delivery strategies show promising perspective in alleviating GBM, while limited blood-brain-barrier (BBB) permeation, short blood half-live accompanied by the poor tumor accumulation and penetration, significantly restrict the therapeutic outcomes. Herein, a versatile super-small zwitterionic nano-system (MCB(S)) based on carboxybetaine (CB) zwitterion functionalized hyperbranched polycarbonate (HPCB) is developed to overcome the brain delivery challenges. After grafting with amino-functionalized IR780 (free IR780), the ultimate paclitaxel (PTX)-encapsulated micelles (MCB(S)-IR@PTX) are precisely activated by near-infrared (NIR) for accelerated drug release and effective combinational GBM therapy. Importantly, MCB(S)-IR@PTX with the crosslinked structure and CB zwitterion prolongs blood-circulation, and CB-zwitterion further facilitates BBB-traversing through betaine/γ-aminobutyric acid (GABA) transporter-1 (BGT-1) pathway. Combined with the benefit of super small-size, MCB(S)-IR@PTX highly accumulates at tumor sites and penetrates deeply, thus efficiently inhibiting tumor growth and strikingly improving survival time in U87MG orthotopic GBM-bearing mouse model. The ingenious nanoplatform furnishes a versatile strategy for delivering therapeutics into the brain and realizing efficient brain cancer therapy. Illustration of the super-small zwitterionic micelle (MCB(S)-IR@PTX) to facilitate blood-circulation, improve BBB-transport and enhance tumor penetration and accumulation for efficient glioblastoma therapy. [Display omitted] •Crosslinked structure and zwitterion-shielding for facilitated blood-circulation•The combination of super-small size and zwitterion-mediated betaine/GABA (γ-aminobutyric acid) transporter-1 (BGT-1) pathway for improved BBB-crossing•The combination of super-small size with zwitterion-produced adsorption-mediated transcytosis for notable tumor accumulation and penetration•PTT-induced accelerated drug release and IR780-triggered hyperthermia for efficient combinational tumor therapy