Gas-filled nanobubbles represent an emerging class of ultrasound-responsive agents designed for targeted drug delivery and enhanced therapeutic efficacy in cancer treatment. These nanostructures consist of a gas core stabilized by a lipid, polymer, or protein shell, enabling them to oscillate or collapse under ultrasound exposure, thereby facilitating drug release and sonoporation. Their unique acoustic properties allow precise spatiotemporal control, making them particularly valuable in ultrasound-mediated therapies.

The shell composition of gas-filled nanobubbles plays a critical role in their stability and responsiveness. Lipid-based shells, commonly composed of phospholipids such as DSPC, DPPC, or PEGylated lipids, provide flexibility and biocompatibility. These lipids form monolayers around the gas core, often filled with perfluorocarbons or sulfur hexafluoride to enhance stability in vivo. Polymer shells, such as those made from poly(lactic-co-glycolic acid) or albumin, offer increased mechanical strength but may reduce acoustic responsiveness. Hybrid shells combining lipids and polymers aim to balance stability with efficient ultrasound-triggered drug release.

Tuning the acoustic response of nanobubbles involves optimizing their size, shell elasticity, and gas core properties. Nanobubbles typically range from 100 to 1000 nm in diameter, with smaller bubbles exhibiting higher resonance frequencies. The viscoelastic properties of the shell influence their oscillation behavior—softer shells promote stable cavitation, while stiffer shells may require higher acoustic pressures for inertial cavitation. By adjusting lipid saturation or incorporating cholesterol, the shell’s mechanical properties can be fine-tuned to achieve desired responses within specific ultrasound frequencies, often between 1 to 10 MHz.

Combining gas-filled nanobubbles with chemotherapeutics enhances localized drug delivery while minimizing systemic toxicity. Drugs can be loaded via encapsulation within the shell, attachment to the surface, or co-administration with nanobubbles. Doxorubicin, paclitaxel, and cisplatin are commonly used chemotherapeutic agents integrated into these systems. Under ultrasound exposure, the mechanical forces generated by bubble oscillation disrupt nearby cell membranes (sonoporation), increasing drug uptake. Studies have demonstrated that ultrasound-triggered release from nanobubbles can improve tumor drug accumulation by up to threefold compared to passive delivery.

The cavitation effects of nanobubbles on tumor vasculature contribute to their therapeutic potential. Stable cavitation generates shear stresses that enhance vascular permeability, promoting extravasation of drugs into tumor tissue. Inertial cavitation, characterized by violent bubble collapse, can induce more significant bioeffects, including microvascular rupture and localized tissue damage. However, controlling inertial cavitation thresholds remains a challenge due to variability in bubble populations and tissue heterogeneity. Excessive inertial cavitation risks unintended vascular damage, while insufficient activity may limit drug release efficacy.

Challenges in controlling inertial cavitation thresholds stem from the dynamic interplay between ultrasound parameters and nanobubble properties. Acoustic pressure, pulse duration, and frequency must be carefully calibrated to avoid premature bubble destruction or inadequate activation. Preclinical studies suggest that real-time monitoring techniques, such as passive cavitation detection, can help optimize ultrasound settings for reproducible outcomes. Additionally, the heterogeneous distribution of nanobubbles within tumors complicates uniform energy deposition, necessitating advanced imaging guidance for precise treatment.

Despite these challenges, gas-filled nanobubbles hold significant promise for improving cancer therapy. Their ability to synergize with ultrasound for controlled drug release and sonoporation offers a non-invasive strategy to enhance treatment precision. Future research will focus on refining shell compositions, optimizing acoustic parameters, and integrating multimodal imaging to facilitate clinical translation. By addressing the complexities of cavitation dynamics and tumor microenvironment interactions, nanobubble-based therapies may unlock new possibilities in targeted oncology treatments.