Engineering Tertiary Lymphoid Structures: Nanomedicine, Bioengineering, and Biomaterials for Precision Immunotherapy

Tertiary lymphoid structures (TLSs) are inducible, ectopic aggregates that mirror the architecture and immunological functions of secondary lymphoid organs, arising in nonlymphoid tissues during chronic inflammation, infection, autoimmunity, and cancer. Their ability to orchestrate local antigen presentation, lymphocyte activation, and germinal center reactions supports their critical roles in both protective immunity and disease pathogenesis. Recent breakthroughs in biomaterials science and nanotechnology have enabled the rational design and manipulation of the stromal and molecular microenvironmental cues necessary for TLS neogenesis, maturation, and modulation. This review collates recent advances in TLS biology with the latest developments in engineering strategies, including the use of hydrogels as scaffolding matrices, nanoparticles, and other microstructured materials, aimed at inducing, supporting, or modulating TLS both in vivo and in vitro. This review critically assess how material properties, cytokine delivery, and cellular engineering can recapitulate or enhance key stromal–immune interactions that drive TLS formation. Furthermore, the translational implications of biomaterial‐ and nanoparticle‐based TLS engineering are examined, highlighting preclinical applications in cancer immunotherapy, autoimmune disorders, and tissue regeneration. Finally, major challenges and future perspectives toward utilizing engineered TLS as customizable, site‐specific immunotherapeutic platforms for precision medicine are discussed.