With the development of nanomedicine technology, stimuli-responsive nanocarriers play an increasingly important role in antitumor therapy. Compared with the normal physiological environment, the tumor microenvironment (TME) possesses several unique properties, including acidity, high glutathione (GSH) concentration, hypoxia, over-expressed enzymes and excessive reactive oxygen species (ROS), which are closely related to the occurrence and development of tumors. However, on the other hand, these properties could also be harnessed for smart drug delivery systems to release drugs specifically in tumor tissues. Stimuli-responsive nanoparticles (srNPs) can maintain stability at physiological conditions, while they could be triggered rapidly to release drugs by specific stimuli to prolong blood circulation and enhance cancer cellular uptake, thus achieving excellent therapeutic performance and improved biosafety. This review focuses on the design of srNPs based on several stimuli in the TME for the delivery of antitumor drugs. In addition, the challenges and prospects for the development of srNPs are discussed, which can possibly inspire researchers to develop srNPs for clinical applications in the future.

Glioblastoma (GBM) is the most aggressive brain tumor, which owns the characteristics of high recurrence, low survival rate and poor prognosis because of the existence of blood brain barrier (BBB) and complicated brain tumor microenvironment. Currently, immunotherapy has attracted much attention on account of favorable therapeutic effect. In this study, we designed a cRGD-modified cancer cell membrane (CM) coated calcium carbonate nanoparticle to deliver interleukin-12 messenger RNA (IL-12 mRNA@cRGD-CM-CaCO₃ NPs). The cRGD-modified CM as the shell can endow the nanoparticles with BBB crossing and tumor homing/homotypic targeting effect in the brain tumor microenvironment. IL-12 mRNA-loaded calcium carbonate nanoparticles as the core allow synergistic immunotherapy of necroptosis-induced immune response and IL-12 mRNA transfection under ultrasound irradiation. The as-prepared biomimetic nanoparticles showed superior target and immunotherapeutic outcomes, suggesting that this biomimetic nanoplatform provides a feasible strategy for promoting BBB-penetrating and antitumor immunity.

As a non-invasive strategy, sonodynamic therapy (SDT) which utilizes sonosensitizers to generate reactive oxygen species (ROS) has received significant interest over recent years due to its ability to break depth barrier. However, intrinsic limitations of traditional sonosensitizers hinder the widespread application of SDT. With the development of nanotechnology, various nanoparticles (NPs) have been designed and used to assist sonosensitizers for SDT. This review first summarizes the possible mechanisms of SDT, then classifies the NPs-assisted sonosensitizers and discusses their biomedical applications in ultrasonography, drug delivery, high intensity focused ultrasound and SDT-based combination treatment. Finally, some challenges and future perspectives of NPs-assisted SDT has also been discussed.

Calcium carbonate nanoparticles have been widely used in biomedicine due to their biocompatibility and biodegradability. Recently, calcium carbonate nanoparticles are largely integrated with imaging contrast and therapeutic agents for various imaging and therapeutic approaches. In this review, we first described the advantages and preparation methods of calcium carbonate nanoparticles, then the state-of-the-art progress of calcium carbonate nanoparticles in diagnosis, treatment and theranostics was summarized. Finally, we discussed the challenges and recommendations for future studies of the calcium carbonate nanoparticles.

Ultrasound with low frequency (20–100 kHz) assisted drug delivery has been widely investigated as a non-invasive method to enhance the permeability and retention effect of drugs. The functional micro/nanobubble loaded with drugs could provide an unprecedented opportunity for targeted delivery. Then, ultrasound with higher intensity would locally burst bubbles and release agents, thus avoiding side effects associated with systemic administration. Furthermore, ultrasound-mediated destruction of micro/nanobubbles can effectively increase the permeability of vascular membranes and cell membranes, thereby not only increasing the distribution concentration of drugs in the interstitial space of target tissues but also promoting the penetration of drugs through cell membranes into the cytoplasm. These advancements have transformed ultrasound from a purely diagnostic utility into a promising theragnostic tool. In this review, we first discuss the structure and generation of micro/nanobubbles. Second, ultrasound parameters and mechanisms of therapeutic delivery are discussed. Third, potential biomedical applications of micro/nanobubble-assisted ultrasound are summarized. Finally, we discuss the challenges and future directions of ultrasound combined with micro/nanobubbles.