The lipid nanomicelles incorporating peptide vaccine and SN38 prodrug potentiate neoadjuvant chemo-immunotherapy

Neoadjuvant regimens often fail to eliminate micrometastases due to profound immunosuppression and the limited immunogenicity of residual tumor cells. In this work, a versatile lipid nanoplatform was engineered to orchestrate potent chemotherapy with in situ neoantigen vaccination. Unlike conventional physical encapsulation, an arginine-modified SN38 prodrug (SN38-Arg) was synthesized to enhance amphiphilicity and facilitate the co-assembly with PEGylated lipids and tumor-specific peptides (HPV16 E7 or Adpgk). This design yields uniform ~115 nm nanomicelles with exceptional stability and > 60% peptide encapsulation efficiency. Mechanistically, these nanomicelles leverage folate-receptor targeting to achieve dual synchronization: SN38-Arg induces Topoisomerase I inhibition and extensive DNA damage, while simultaneously promoting dendritic cell maturation and antigen cross-presentation. In neoadjuvant murine models of HPV+ TC-1 and MSI-high MC38 tumors, a brief preoperative course of SFE/SFA not only significantly debulked primary tumors but, critically, prevented postsurgical recurrence of treated cohorts and established long-term protective memory T cell reservoirs. This was accompanied by a remodeled tumor immune microenvironment marked by elevated CD8+ T cell infiltration and the reduction of regulatory T cells and MDSCs, all without discernible systemic toxicity. This work establishes a clinically translatable, off-the-shelf nanomicellar strategy that integrates SN38-based chemotherapy with peptide vaccination, offering a compelling avenue to improve pathological complete response rates and long-term disease-free survival in surgical oncology.