Strategically targeting lymph nodes (LNs) to orchestrate the initiation and regulation of adaptive immune responses is one of the most pressing challenges in the context of vaccination. Herein, a series of polymer-TLR agonist conjugates (PTACs) is developed to investigate the impact of dendritic-topological characteristics on their LN targeting activity in vivo, and their molecular weight (MW) on their pharmacokinetics in support of their LN homing. Notably, the dendritic 6-arm PTAC with a MW of 60 kDa (6A-PTAC-60k) rapidly delivered cargo to draining LNs after administration to peripheral tissues. Specifically, this topologic structure ameliorated the targeting behavior within lymphatic vessels and LNs, including an elevated amount of TLR7/8 agonist delivered to the LNs, an improved distribution pattern among barrier cells and immune cells, increased permeability, and prolonged retention. Furthermore, the 6A-PTAC-60k formulation induced broad antibody and T cell responses, enhancing vaccine immunogenicity and suppressing tumor growth. The results revealed that both the topology and MW of polymers are crucial factors for immunoadjuvant distribution and their functional activity in the draining LNs, which, in turn, enhanced the immunogenicity of the vaccine formulation. This study may provide a chemical and structural basis for optimizing the design of immunoadjuvant delivery systems.© 2025 Wiley‐VCH GmbH.