Deformable Albumin-Hitchhiking Nanocarriers Loaded in Gelatin Microspheres for Immune Cell Recruitment and Cancer Immunotherapy.

Immune delivery and activation in lymph nodes (LNs) provide boosted cancer nanovaccine efficacy, but tumor-induced immunosuppression in lymph nodes compromises nanovaccine efficacy. Toward that end, we engineered BIO-GEM, a hierarchically structured biomimetic lymph node (bLN) platform comprising genipin-crosslinked gelatin microspheres (GEM) encapsulating deformable albumin-hitchhiking nanoemulsions (BIO, generated with bovine albumin, imiquimod adjuvant, and OVA antigen). Compared to conventional microparticles used for immune cell recruitment, BIO-GEM forms antigen-rich depots that better recruit antigen-presenting cells (APCs) and T cells, creating an immunostimulatory niche for in situ T-cell priming. Collagenase-responsive degradation of GEM triggers sustained release of BIO, which targets LNs via the albumin-hitchhiking pathway. This spatiotemporal delivery strategy synergizes bLN-resident immune activation with LN-directed antigen trafficking, yielding high CD8+ T-cell infiltration at injection sites, dendritic cell maturation, and elicitation of antigen-specific cytotoxic T cells. In multiple B16 murine melanoma models, BIO-GEM significantly suppressed tumor growth and extended the survival of mice. Intradermal vaccination was more efficacious than subcutaneous or intramuscular injection routes.