Zhilin Liu

The tumor vascular barrier restricts the penetration of antibody‐conjugated nanomedicine, severely limiting its therapeutic efficacy. Selective delivery of nitric oxide (NO) to tumors can modulate vascular permeability, thereby enhancing the penetration of antibody‐conjugated nanomedicine. Herein, we developed an ultrasound‐responsive NO‐releasing material, named HA‐SNO, based on a hyaluronic acid backbone, which releases NO upon exposure to ultrasound waves. After systemic administration of HA‐SNO, tumor‐localized release of NO was achieved using a focused ultrasound system operating at a low intensity (1 MHz, 2.0 W/cm ² , 50% duty cycle). The released NO induced vasodilation and disrupted the tumor vascular barrier, thereby promoting extravasation and more homogeneous intratumoral distribution of HER2‐targeted antibody–conjugated nanomedicine (HER2–SN38). This strategy exhibited significantly enhanced anti‐tumor efficacy, with a tumor inhibition rate of 97.67%. These findings highlight the potential clinical utility of ultrasound‐triggered tumor‐selective delivery of NO in overcoming vascular barriers to drug delivery.

Ultrasound has emerged as a versatile clinical tool due to its high tissue penetration and ability to deliver energy precisely to targeted areas. Increasing attention is now focused on its ability to induce chemical transformations of compounds in vivo and the underlying mechanisms therein. Here, we report a new ultrasonic chemistry mechanism in which low-intensity ultrasound facilitates the single-electron reduction of aromatic azides, converting them to bioactive amines. This transformation is especially efficient with aromatic compounds bearing strong electron-withdrawing groups or minimal natural charge. Using azide-masked resiquimod (R848-N3) as a model, we demonstrate that ultrasound induces a reduction reaction mediated by β-nicotinamide adenine dinucleotide disodium salt hydrate, with riboflavin tetrabutyrate serving as an electron transfer catalyst, significantly enhancing reaction rates. In a colon cancer model, nanoparticles co-loaded with R848-N3 and riboflavin tetrabutyrate achieved a remarkable 99.0% tumor suppression rate and a 66.7% cure rate when paired with low-intensity ultrasound. This study reveals ultrasound as an effective switch for prodrug activation, laying the foundation for azide-masked compounds as a new class of ultrasound-responsive cancer therapeutics.

Ultrasound (US) has been applied in clinical practice for its non-invasive and high selectivity. However, it is difficult to achieve a satisfactory anti-tumor effect with US alone. Meanwhile, the use of US therapy alone can exacerbate tumor hypoxia. In this study, we prepared hypoxia-activated 6-diazo-5-oxo-L-norleucine (DON) prodrug nanoparticles (HDON-NPs) to improve US therapeutic effects. In an H22 murine liver cancer model, US therapy selectively disrupted tumor blood vessels, leading to increased tumor hypoxia and a 1.67-fold increase in the expression of nitroreductase (NTR). The combination therapy of US and HDON-NPs demonstrated a synergistic effect, resulting in a tumor suppression rate (TSR) of 90.2% ± 6.4%, which was 5.93-fold higher than that of US therapy alone. The combined treatment selectively blocked the glutamine metabolism of the tumor cells while simultaneously activating the T cells in the tumor microenvironment, thereby exerting a robust anti-tumor effect.

Interleukin-2 (IL-2) used in multiple sclerosis (MS) therapy modulates the balance between regulatory T (Treg) cells and effector T (Teff) cells. However, the off-target activation of Teff cells by IL-2 limits its clinical application. Therefore, a rapidly prepared immunoswitch nanomodulator termed aT-IL2C NPs was developed, which specifically recognized Treg cells with high TIGIT expression thanks to the presence of an anti-TIGIT and an IL-2/JES6-1 complex (IL2C) being delivered to Treg cells but not to Teff cells with low TIGIT expression. Then, IL2C released IL-2 due to the specific expression of the high-affinity IL-2 receptor on Treg cells, thus enabling the active targeting and selective proliferation of Treg cells. Moreover, the anti-TIGIT of aT-IL2C NPs selectively inhibited the proliferation of Teff cells while leaving the proliferation of Treg cells unaffected. In addition, since the IL-2 receptor on Teff cells had medium-affinity, the IL2C hardly released IL-2 to Teff cells, thus enabling the inhibition of Teff cell proliferation. The treatment of experimental autoimmune encephalomyelitis (EAE) mice with aT-IL2C NPs ameliorated the severity of the EAE and restored white matter integrity. Collectively, this work described a potential promising agent for effective MS therapy.

Tumor-active-targeting drugs such as antibody–drug conjugates have emerged as promising accurate therapeutic agents. However, their complex preparations risk compromising the targeting ability of the fragment antigen binding (Fab) region and promote aggregation over long-term storage. Here, we propose a tumor-active-targeting nanomedicine, aPDL1–PLG–MMAE, that effectively targets programmed death-ligand 1 (PDL1) high-expressing tumors and delivers monomethyl auristatin E (MMAE). aPDL1–PLG–MMAE consists of an anti-PDL1 monoclonal antibody (aPDL1) and poly(L-glutamic acid) (PLG) grafted Fc-III-4C peptide/Val–Cit–PAB–MMAE (Fc–PLG–MMAE). Fc–PLG–MMAE was obtained by conjugating the Fc-III-4C peptide and Val–Cit–PAB–MMAE to PLG via amide condensation. The strong affinity between the fragment crystallizable (Fc) region of aPDL1 and the Fc-III-4C peptide enabled aPDL1 and Fc–PLG–MMAE to self-assemble into aPDL1–PLG–MMAE after four hours of coincubation in PBS. As this nanomedicine can be quickly prepared for immediate use, the required antibodies can be stored separately from the Fc–PLG–MMAE portion for extended periods, which also facilitates transport. Moreover, aPDL1–PLG–MMAE demonstrated robust tumor recognition and targeting effects on MC38 colon cancer cells, resulting in potent therapeutic efficacy without significant toxicities.