Acoustic Cavitation-Enhanced Remodeling of Lymph Node Microenvironment Enables Deep Infiltration for Potent Cancer Vaccination

The efficacy of peptide-based tumor vaccines is often constrained by the size-exclusion barrier of the subcapsular sinus (SCS), which restricts infiltration of macromolecules into the lymph node (LN) parenchyma essential for T-cell priming. Here, inspired by the clinical contrast agent Sonazoid, we developed an ultrasound-assisted vaccine platform with tunable phase-transition behavior for active modulation of the LN microenvironment. The system integrates phosphoserine-decorated lipid chemistry to promote cell-mediated LN trafficking, a covalently conjugated adjuvant–antigen construct for synchronized immunostimulation, and liquid-state perfluorocarbon nanodomains programmed for ultrasound-triggered liquid–gas transition. Upon localized ultrasound irradiation, the chemically programmed phase transition triggers cargo release, while the resultant acoustic cavitation generates transient openings in the SCS endothelium. This process enables deep parenchymal infiltration of vaccine components that would otherwise be excluded. Beyond the physical barrier disruption, RNA sequencing reveals that acoustic stimulation drives both structural and immunological reprogramming of LN into an immune-permissive niche. By synergizing mechanical stimulation with biological modulation, this strategy induces benign and persistent LN expansion, amplifies anti-tumor T-cell responses, and establishes durable immunological memory, resulting in both prophylactic and therapeutic outcomes. This approach is versatile across both model antigens and neoantigens, offering a bio-inspired, two-stage LN-targeted delivery strategy that serves as a framework for designing more effective therapeutic vaccines.