Tetrandrine-based in situ vaccination via multifunctional Mn²⁺-hyaluronic acid hydrogel loading gelatinase-responsive nanoparticles.

In situ tumor vaccination (ISV) has emerged as a promising strategy for converting tumors into endogenous vaccine depots, but its application in breast cancer remains limited by poor intratumoral drug retention and insufficient microenvironment remodeling. Here, we developed an injectable Mn²⁺-coordinated hyaluronic acid hydrogel embedding gelatinase-responsive tetrandrine nanoparticles (TETNPs@Gel) as an MRI-trackable local ISV platform. TETNPs@Gel exhibited biphasic, pH-responsive drug release, accelerating tetrandrine liberation under mildly acidic conditions while limiting premature leakage at physiological pH. Mn incorporation provided positive T1-weighted contrast and enabled longitudinal monitoring of depot retention in vivo. In orthotopic 4T1 tumors, TETNPs@Gel significantly inhibited tumor growth, prolonged survival, and caused no obvious systemic toxicity. In a bilateral 4T1 model, local treatment also suppressed the growth of untreated distant tumors, reduced pulmonary metastatic burden, and improved survival, indicating a systemic antitumor effect. Mechanistically, TETNPs@Gel enhanced dendritic-cell maturation and intratumoral CD8⁺ T-cell infiltration, increased C3a and C5a levels, and induced vascular/perivascular remodeling. Bulk and single-cell transcriptomic analyses further revealed complement-associated activation, extracellular-matrix remodeling, and enrichment of antigen-presenting and inflammatory macrophage programs. Thus, TETNPs@Gel functions as an in situ nanovaccine rather than a conventional cytotoxic formulation, in which controlled tetrandrine release couples direct tumor-cell killing with vascular and immune re-education, offering a potentially generalizable platform for localized immunochemotherapy in solid tumors.