Phase change nanodroplets: Challenges and clinical potential

Phase change nanodroplets (PCND) consist of a liquid fluorocarbon core, which vaporizes into gas upon energy excitation, and a stabilizing shell. Through this phase-change property, PCND combine nanoparticle-like stability and pharmacokinetics, such as tissue extravasation and uptake by the mononuclear phagocyte system, with distinctive microbubble-like capabilities, namely ultrasound contrast enhancement and energy-triggered therapeutic action. PCND serve both as highly sensitive imaging agents, from molecular imaging to high-resolution vascular mapping, and as versatile therapeutics, used for example for thrombolysis, tissue ablation, biofilm removal, immunomodulation, and drug delivery. This review article provides a focused review of the biological behavior of PCND, including blood half-life, biodistribution, clearance pathways, and tumor accumulation, following a brief overview of the key physicochemical features that shape their in vivo fate. By comparing data across studies, we identify major inconsistencies in reported pharmacokinetics and highlight critical knowledge gaps, particularly regarding safety data. We further summarize advances in PCND-enabled imaging and therapy, and propose strategies to strengthen formulation design, biological evaluation, and stimulation protocols to support future clinical translation. Overall, PCND hold strong potential as a versatile theranostic platform. Continued systematic and clinically focused research is expected to accelerate their path toward clinical translation.