Pulsed Microwave‐Induced Thermoacoustic Shockwave for Precise Glioblastoma Therapy with the Skin and Skull Intact

Glioblastoma has a dismal prognosis and is a critical and urgent health issue that requires aggressive research and determined clinical efforts. Due to its diffuse and infiltrative growth in the brain parenchyma, complete neurosurgical resection is rarely possible. Here, pulsed microwave‐induced thermoacoustic (MTA) therapy is proposed as a potential alternative modality to precisely and effectively eradicate in vivo orthotopic glioblastoma. A nanoparticle composed of polar amino acids and adenosine‐based agonists is constructed with high microwave absorbance and selective penetration of the blood‐brain barrier (BBB) at the tumor site. This nanoparticle can activate the adenosine receptor on the BBB to allow self‐passage and tumor accumulation. The nanoparticle converts absorbed microwaves into ultrasonic shockwaves via the thermoacoustic cavitation effect. The ultrasonic shockwave can mechanically destroy tumor cells within a short range with minimal damage to adjacent normal brain tissue due to the rapid decay of the ultrasonic shockwave intensity. The deep tissue penetration characteristics of the microwave and the rapid decay of the ultrasonic shockwave make MTA therapy a promising glioblastoma cure including intact skin and skull. CGS (a class of A2AAR agonists) opens the blood‐brain barrier (BBB) for dendrimers (Den)‐CGS/cyclic [RGDyK] peptides (RGD)/lysine (Lys) to cross the BBB and enter glioblastoma. RGD on Den‐CGS/RGD/Lys can target glioblastoma accurately. Lys absorbs pulsed microwave energy and stimulates the thermoacoustic cavitation effect, which generates strong acoustic shockwaves leading to mechanical damage to glioblastoma cells with minimal damage to adjacent normal tissues due to the rapid attenuation of the acoustic shockwave.