Explosible nanocapsules excited by pulsed microwaves for efficient thermoacoustic-chemo combination therapy

Microwave irradiation is a powerful non-invasive approach for treating deep-seated diseases in a clinical setting. Pulsed microwave-induced thermoacoustic cavitation allows precise cancer treatment with microwave-absorbing materials. This differs from the traditional continuous microwave-induced thermotherapy which may be harmful to off-target tissues. Here we first report the integration of thermocavitation and cytoplasmic drug release into highly explosible cell-penetrating nanocapsules for effective tumor inhibition under pulsed microwave irradiation. The nanocapsules were formulated from arginine-tethered reduction-responsive copolymers, P(ArgMA-co-DMA)-b-PPOPMA, microwave-absorbing AB and chemotherapeutic DOX using a double-emulsion method. The nanocapsules were internalized by cancer cells rapidly via major energy-independent pathways. Upon pulsed microwave irradiation, AB absorbed energy to generate a giant thermoacoustic shockwave, simultaneously decomposing into carbon dioxide and ammonia which enforced the cavitation damage effect. The thermoacoustic shockwave and gas burst also mechanically disrupted the intracellular organelles resulting in high-ratio cell necrosis and promoted the cytosolic release of DOX into the nucleus to initiate cell death. Importantly, in vivo results demonstrated significantly suppressed tumor growth by the pulsed microwave-triggered thermocavitation and drug release, and minimal systemic toxicity from the microwave treatment. Therefore, our study provides a new strategy for effectively engineering pulsed microwave-responsive nanomaterials for smart cancer therapy.