New Nanoparticle System Uses Ultrasound for Precise Drug Delivery

On-demand controlled delivery has long sounded like a dream: inject a drug into the blood and activate it exactly where and when the effect is needed. The Stanford and partners team has demonstrated a working platform that does this in simple and translatable pharma language: acoustically activated liposomes (AAL), with sucrose added to the core. This safe, widely used excipient in medicines changes the acoustic properties of the liposome's water "filling", and low-intensity pulsed ultrasound makes the membrane briefly "breathe", releasing a dose of the drug without heating the tissue. In rats, ketamine was "turned on" in specific areas of the brain and a local anesthetic near the sciatic nerve, getting the effect in the right place, without unnecessary side effects.

Background of the study

Targeted pharmacology has long been stuck in two main problems: where to deliver the drug and when to activate it. In the brain, this is hampered by the blood-brain barrier, on peripheral nerves - the risk of systemic side effects of local anesthetics and the "spread" of the blockade across the tissues. We need a tool that would allow the drug to be administered by the usual intravenous route, and then turn on its action pointwise - in a few millimeters of the desired cortex or around a specific nerve trunk - and only for the duration of the procedure.

Physical "remote controls" for drugs have already been tried: light (photoactivation) is limited by the depth of penetration and scattering; magnetic and heat-sensitive carriers require specific equipment and often heating of tissues, which complicates the clinic; microbubbles with focused ultrasound are capable of opening the BBB, but this is accompanied by cavitation and microdamage, which are difficult to dose and safely standardize. At the other extreme are classic liposomes: they are compatible with pharmaceutical technologies and are well tolerated, but too stable to deliver a "dose impulse on command" without rough thermal or chemical stimulation.

Hence the interest in acoustic activation without heating and cavitation. Low-intensity pulsed ultrasound penetrates deeply, has long been used in medicine (neuromodulation, physiotherapy), is well focused and scalable. If the carrier is made so that short acoustic pulses temporarily increase the membrane permeability and release part of the load, it is possible to obtain a "drug uncaging" mode - controlled release - without thermal stress and rupture of vascular walls. The key subtlety here is the composition of the particle "core": the acoustic properties and response to ultrasound depend on it.

And finally, the “translational filter”: even brilliant physics is of little use if the platform relies on exotic materials. For a clinic, it is critical that the carrier is assembled from GRAS components, withstands cold logistics, is compatible with mass production and quality standards, and the ultrasound modes fit into the usual ranges of medical devices. Therefore, the focus is now shifting to “smart” versions of already proven lipid carriers, where a small change in the internal environment (for example, due to safe excipients) turns the liposome into an “ON” button for ultrasound - with potential applications from pinpoint anesthesia to targeted neuropsychopharmacology.

How it works

• A buffer containing 5% sucrose is poured into the liposome: this increases the acoustic impedance and creates an osmotic gradient, which accelerates the release of molecules when exposed to ultrasound.
• Focused ultrasound (approximately 250 kHz, duty cycle 25%, PRF 5 Hz; peak negative pressure in tissues ~0.9-1.7 MPa) is applied to the target area, and the liposome “opens” – drug uncaging.
• An important detail: no heating is required (at 37°C the effect is even higher, but it also works at room temperature), and the “sugar” approach itself uses GRAS excipients and standard liposome production processes.

What exactly was shown

• In vitro: the platform works with four drugs at once:
  • Ketamine (anesthetic/antidepressant);
  • Ropivacaine, bupivacaine, lidocaine (local anesthetics).
    Adding 5-10% sucrose inside gave ~40-60% release per minute of standard sonication; 10% is more powerful, but has worse stability, so the optimum is 5%.
• In the brain (CNS): After intravenous infusion of SonoKet (ketamine in AAL), ultrasound to the mPFC or retrosplenial cortex increased drug levels at the target site versus contralateral/sham control and induced electrophysiological changes without tissue damage. There was no BBB opening or evidence of cavitation injury.
• In peripheral nerves (PNS): SonoRopi formulation (ropivacaine in AAL) with external irradiation of the sciatic nerve area produced local blockade on the treated side, without ECG changes and without histological damage in the tissue.

Numbers to Remember

• Ultrasound parameters: 250 kHz, 25% duty, 5 Hz PRF; in the brain ~0.9-1.1 MPa, in vitro tests up to 1.7 MPa; exposure “window” - 60-150 s.
• Stability: At 4°C, AALs retained size/polydispersity for at least 90 days (DLS ~166-168 nm, PDI 0.06-0.07).
• Core physics: the "opening" force is linear with the acoustic impedance of the internal environment (correlation r² ≈ 0.97 for equiosmolar NaCl/glucose/sucrose buffers).

How is this better than previous “ultrasonic” carriers?

• Free of PFCs and gas bubbles: lower risk of cavitation and instability.
• Without heating the tissue: no need for “heavy” temperature conditions or jewelry requirements for equipment.
• Venous pathway, standard pharma: size ~165 nm, familiar lipid components and sucrose as a key to acoustic sensitivity.

Why does the clinic need this?

• Neuropsychiatry: ketamine-like molecules are effective but noisy in side effects. Targeting mPFC/other regions would theoretically produce effects with less dissociation/sedation/sympathomimetic effects.
• Pain relief and regional anesthesia: sono-controlled nerve block is "high on action, low on systemic", promising less cardio- and CNS toxicity.
• A platform, not a one-off: the approach is transferable to other liposomes/polymeric “liquid-nuclear” carriers and, potentially, to a variety of drugs.

What about safety and pharmacokinetics?

• In rats, the histology of the brain/end tissues was without damage; in experiments with “bad” parameters, there were microhemorrhages, but not in working modes.
• In blood, more metabolites and less unmetabolized drug were observed in parenchymal organs with AAL, consistent with uptake/metabolism of particles by the liver at baseline and release to targets during sonication.

Where is the "spoon of skepticism" here?

• This is a preclinical study in rodents; liver uptake kinetics and baseline 'leakage' without ultrasound require optimization.
• Moving to humans will simplify the metabolic details (lower hepatic blood flow), but safety/dosimetry confirmation is mandatory.
• The selection of ultrasonic modes and excipients (which shift the acoustics more strongly, but do not destroy stability) is the task of the next series of works.

Conclusion

The "sugar filling" of liposomes turns ultrasound into an "ON" button for drugs, rather than a crude "sledgehammer." As a result, the drug can be turned on locally - in millimeter zones of the brain or along a nerve - and turned off in the rest of the body. This is not magic, but acoustic and osmotic engineering - and, judging by the results, very close to becoming a routine tool of targeted pharmacology.

Source: Mahaveer P. Purohit, Brenda J. Yu, Raag D. Airan, et al. Acoustically activatable liposomes as a translational nanotechnology for site-targeted drug delivery and noninvasive neuromodulation. Nature Nanotechnology (published 18 August 2025, open access). DOI: 10.1038/s41565-025-01990-5.