Mannose-functionalized thermoresponsive microneedles for enhanced antigen delivery and immune activation.

Stimuli-responsive microneedles (MNs) constitute a promising vaccine delivery platform through spatiotemporally programmed antigen release, enabling innate immunity-synchronized delivery, microenvironment-tunable immunogenicity, and controlled lymphoid targeting for enhanced vaccine potency. Herein, we developed thermoresponsive MNs using a hybrid matrix (HNM) of mannose-functionalized poly(N-isopropylacrylamide) (PNIPAM) and hyaluronic acid (HA) for controlled antigen delivery and immune activation. The MNs were fabricated via a template-based method, with mannose-conjugated PNIPAM enabling temperature-triggered release above its lower critical solution temperature (LCST) and accelerated release at physiological temperature, while HA enhances mechanical integrity (failure force: 0.77 N needle-1) and biodegradability. In vitro and in vivo release studies demonstrated temperature-dependent ovalbumin (OVA) release (2.14 µg/14 min at 37 °C; 67.3% within 24 h in vivo) and prolonged retention (72 h). Intracellular co-localization confirmed mannose receptor-mediated uptake of the antigen-carrier complex. Flow cytometry revealed 84.0% dendritic cell recruitment and 67.6% splenic lymphocyte proliferation. Furthermore, antigen-loaded HNM-MNs demonstrated superior therapeutic efficacy in both the B16-F10 melanoma model and influenza B hemagglutinin (Hem) viral challenge model. This work introduces a dual-functional platform integrating mannose-targeted delivery and thermoresponsive release, offering an effective strategy to improve subunit vaccine efficacy by enabling precise antigen release and enhanced immune activation.