Therapeutic vaccines represent a promising strategy for cancer immunotherapy and have garnered considerable attention [[1], [2], [3], [4]]. Despite the advancement of several candidates into clinical trials, their overall efficacy remains limited, primarily due to poor antigen delivery and inefficient cytosolic transport in dendritic cells (DCs), which result in suboptimal cross-presentation and low immunogenicity [[5], [6], [7], [8]]. Under physiological conditions, vaccine antigens need to be drained to lymph nodes (LNs) and effectively captured by local antigen-presenting cells (APCs) [[9], [10], [11]]. However, soluble protein antigens exhibit poor uptake by APCs and are often degraded within lysosomes following endocytosis, thereby hindering cytosolic delivery and impairing antigen cross-presentation [[12], [13], [14]]. Therefore, the development of vaccine carriers capable of efficient delivery of tumor antigens to DCs has become a key breakthrough in tumor vaccine research and development.

The rapid development of nanotechnology has opened new avenues for vaccine design [[15], [16], [17], [18]]. Among these, polymeric nanovaccines have garnered significant interest due to their tunable architectures and multifunctionality [[19], [20], [21]]. For instance, poly(lactic-co-glycolic acid) (PLGA) nanoparticles can encapsulate antigens to protect them from enzymatic degradation and prolong immune stimulation [[22], [23], [24]]. The ultra-pH-sensitive poly(cyclodextrin-7-amine) (PC7A) has been reported to promote type I interferon responses in DCs, through modulation of the stimulator of interferon genes (STING) pathway [[25], [26]]. Furthermore, polyethyleneimines (PEI) modified with hydrophobic moieties have demonstrated improved DC maturation through innate immune activation [[27], [28]]. Recent advances have also explored viromimetic polymeric vaccines, which mimic virus-like structures to enhance immune response and improve cancer vaccine efficacy [[29], [30]]. Nevertheless, most tumor antigens, including peptides and proteins, possess complex structures, are prone to enzymatic degradation, and exhibit low loading efficiencies, posing significant challenges for delivery systems in overcoming biological barriers and achieving effective anti-tumor immune responses [[31], [32]]. Although polymer carriers show great promise for vaccine delivery, integrating multiple immunological functions into a single platform remains challenging. Therefore, designing nanocarriers capable of high antigen loading, efficient cytosolic delivery and coordinated immune stimulation remains challenging for cancer vaccine.

Octopuses capture prey through their soft, flexible tentacles and the numerous suckers. Inspired by the octopus's multivalent prey-capture mechanism utilizing tentacles and adhesive suckers, we developed a polymeric nanovaccine platform integrating high antigen-loading capacity, efficient cytosolic delivery, and self-adjuvant properties (Scheme 1). The nano-octopus vaccine was constructed by co-assembling the antigen with imidazole-functionalized fluorinated polyethyleneimine (PEI-F-M) and Mn2+. This design draws inspiration from the multivalent capture strategy of octopus tentacles: the PEI backbone serves as tentacle-like arms, while midazole-Mn2+ units mimic suction cups, enabling stable antigen capture via electrostatic, coordination, and hydrophobic interactions. After subcutaneous injection, the nanovaccine efficiently accumulates in draining lymph nodes (DLNs) and is actively internalized by DCs, promoting cytosolic delivery of antigens and enhancing DCs maturation and antigen cross-presentation. Concurrently, the intracellular release of Mn2+ activates the STING pathway, driving robust immune activation. Functionally, the nano-octopus vaccine induces strong antigen-specific CD8+ T cell responses and promotes potent antitumor effects. In summary, this multifunctional polymeric nanovaccine integrates STING activation, biomimetic antigen capture, and imidazole-mediated endosomal escape, offering a promising approach for cancer vaccination.