Nanovaccines represent a transformative approach in cancer immunotherapy, leveraging engineered nanoparticles to deliver tumor antigens and immunostimulatory adjuvants with high precision. These systems enhance antigen presentation, stimulate robust immune responses, and induce long-term immunological memory. Key platforms include poly(lactic-co-glycolic acid) (PLGA) nanoparticles and liposomes, which protect payloads from degradation and facilitate targeted delivery to antigen-presenting cells (APCs). Coupled with Toll-like receptor (TLR) agonists as adjuvants, nanovaccines activate dendritic cells (DCs) and promote cross-presentation of tumor-associated antigens (TAAs) or neoantigens via major histocompatibility complex (MHC) class I and II pathways.

PLGA nanoparticles are widely used due to their biodegradability, controlled release kinetics, and versatility in encapsulating antigens and adjuvants. Studies demonstrate PLGA particles with diameters between 100–200 nm are efficiently internalized by DCs, leading to enhanced MHC-I presentation and CD8+ T-cell activation. Co-delivery of TLR agonists like poly(I:C) (TLR3) or CpG oligodeoxynucleotides (TLR9) further amplifies DC maturation and cytokine secretion. Liposomal systems, on the other hand, excel in membrane fusion and cytosolic delivery, enabling direct antigen access to the cytoplasm for proteasomal processing and MHC-I loading. Cationic liposomes also promote lymph node accumulation, critical for priming naïve T cells.

Antigen presentation pathways are central to nanovaccine efficacy. Exogenous antigens encapsulated in nanoparticles are taken up by APCs via endocytosis or phagocytosis. PLGA nanoparticles escape endosomal degradation through proton-sponge effects, while liposomes fuse with endosomal membranes, releasing cargo into the cytosol. Processed antigens are then loaded onto MHC-I (cross-presentation) or MHC-II (for CD4+ T-cell activation). TLR agonists concurrently stimulate pattern recognition receptors, upregulating co-stimulatory molecules (CD80, CD86) and cytokines (IL-12, IFN-γ), fostering a Th1-polarized response essential for antitumor immunity.

The route of administration significantly impacts immune activation. Subcutaneous injection facilitates nanoparticle uptake by dermal DCs and Langerhans cells, which migrate to draining lymph nodes. This route is clinically practical but may exhibit variable biodistribution. Direct lymphatic delivery, via intranodal or intralymphatic injection, bypasses peripheral tissue barriers, ensuring rapid APC engagement. Comparative studies in murine models show lymphatic delivery enhances antigen-specific T-cell responses by 2–3 fold over subcutaneous administration, though technical challenges limit widespread clinical adoption.

Clinical trials evaluating neoantigen nanovaccines reveal promising outcomes. In melanoma patients, PLGA-based vaccines targeting mutant BRAF or NY-ESO-1 antigens induced detectable CD8+ T-cell responses in 60–70% of participants, with partial tumor regression observed in a subset. Liposomal vaccines incorporating personalized neoantigens and CpG achieved similar response rates, with durable memory T-cell formation persisting beyond 12 months. Notably, combination therapies pairing nanovaccines with immune checkpoint inhibitors (anti-PD-1) demonstrate synergistic effects, doubling objective response rates in some trials.

Immune memory induction remains a critical benchmark for nanovaccine success. Nanoparticles promote the generation of central memory (TCM) and effector memory (TEM) T cells through sustained antigen release and prolonged DC stimulation. PLGA systems releasing antigens over 7–14 days elicit higher frequencies of TCM cells compared to bolus injections. Adjuvant selection also influences memory; TLR4 agonists like monophosphoryl lipid A (MPLA) preferentially expand CD8+ TCM populations, while TLR7/8 agonists drive TEM differentiation.

Despite progress, challenges persist in optimizing nanovaccine design. Batch-to-batch variability in nanoparticle synthesis can affect immune outcomes, and scaling up production while maintaining consistency remains a hurdle. Additionally, the immunosuppressive tumor microenvironment may limit effector T-cell infiltration, necessitating combinatorial strategies. Future directions include multicomponent nanoparticles co-delivering antigens, adjuvants, and immune modulators (e.g., IDO inhibitors) to counteract resistance mechanisms.

In summary, nanovaccines harnessing tumor antigens and TLR agonists offer a potent platform for cancer immunotherapy. Through rational design of nanoparticle carriers and delivery routes, these systems achieve precise immune activation, robust memory formation, and improved clinical responses. Continued refinement of materials, antigen selection, and combination regimens will further advance their therapeutic potential.