Background Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) exhibit poor survival due to tumor microenvironment (TME) barriers and systemic toxicity of chemo-immunotherapy associated with chemo-immunotherapy. Methods An injectable thermoresponsive hydrogel was engineered by crosslinking D-α-tocopheryl polyethylene glycol succinate (TPGS) with Na₂CO₃ (15 % w/v TPGS: 9 % w/v Na₂CO₃). This platform co-encapsulated doxorubicin-loaded nanoparticles (DOX NP) synthesized via PEI-cis-aconitic acid conjugation and CpG-loaded adjuvant nanoparticles (CpG NP) prepared through genipin-mediated PEI crosslinking. The hydrogel exhibited rapid temperature-triggered gelation, shear-thinning injectability, and a macroporous architecture that enabled dual drug retention and immune cell infiltration. Results In vitro , the hydrogel provided the sustained release of DOX NP with pH-responsive acceleration in acidic TME. In vivo , localized delivery of Gel-DOX NP-CpG NP significantly suppressed tumor growth ( p < 0.05) and enhanced cytotoxic CD8 + T-cell infiltration in TME (3.1-fold) and spleens (2.4-fold). RNA sequencing revealed 88 immune-related differentially expressed genes, including downregulated immunosuppressors and enriched cytokine pathways. Conclusion This TPGS/Na₂CO₃ hydrogel platform coordinates chemotherapy-induced immunogenic cell death (DOX NP) with CpG-driven innate immunity, overcoming TME barriers to enhance localized and systemic anti-tumor responses in HNSCC.
Liver cancer is the most common malignant tumor and liver cancer immunotherapy has been one of the research hotspots. To induce antigen-specific antitumor immune responses against liver cancer, we developed antigen and adjuvant co-delivery nanovaccines (APPCs). Polyanionic alginate (ALG) and polycationic polyethyleneimine (PEI) were utilized to co-deliver a glypican-3 peptide antigen and an unmethylated cytosine-phosphate-guanine (CpG) adjuvant by electrostatic interactions. A cellular uptake study confirmed that APPC could promote antigen and adjuvant uptake by dendritic cells (DCs). Importantly, APPC facilitated the endosomal escape of the peptide for antigen delivery into the cytoplasm. In addition, APPC showed significant stimulation of DC maturation in vitro. APPC could also efficiently prime DCs and induce cytotoxic T lymphocyte responses in vivo. The in vitro cell viability assay and the in vivo histocompatibility showed that APPC was non-toxic within the tested concentration. This study demonstrates that the peptide antigen and the CpG adjuvant co-delivery nanovaccine have potential applications in liver cancer immunotherapy.
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