A Single-dose Vaccine Using Ultrasound-responsive Hydrogel for Controlled Antigen Release and Enhanced Immunization Efficacy

Sustained antigen release from delivery systems is a pivotal strategy to enhance vaccine-induced immune responses, primarily by mimicking the antigen exposure kinetics of natural infections to synchronously boost humoral and cellular immunity. However, the absence of an “antigen boost” effect in current approaches stands as a critical bottleneck, limiting the intensity and durability of immune responses. To address the critical gap of insufficient antigen boosting in sustained-release vaccine platforms, we engineered an ultrasound-responsive hydrogel (URH) with diselenide-functionalized 4-arm PEG-ONH₂ (4-arm PEG-Se-Se-ONH₂), 4-arm PEG-ONH₂ and ODEX. Leveraging its exceptional ultrasonic sensitivity, the URH enables timely controlled, multiple-boost antigen release both in vitro and in vivo, overcoming the limitations of conventional sustained-release systems. With the multiple boost release mode triggered by ultrasound, the immune response in lymph nodes was significantly stronger than that in sustained release group without ultrasonic trigger. At the same time, it also greatly improved the humoral immunity level, URH+US-OVA elicited 7.5×10⁴-fold higher anti-OVA IgG titers over commercial Al-OVA vaccines and 440-fold higher than URH-OVA vaccines at day 40 post-vaccination, while the levels of blood routine and inflammatory factors were within the normal range, which proved that the safety of URH vaccines. The results support that the antigen release mode is a key factor affecting the immunological efficacy of vaccines, and URH can be modularized to regulate the multiple boost antigen release mode.