2025/11/22 by Ting Wang, Zhiqing Pang · 1 voice
Engineering · Immunology and Microbiology · Biochemistry, Genetics and Molecular Biology · #Nanoplatforms for cancer theranostics #Immunotherapy and Immune Responses #Extracellular vesicles in disease
paper · pdf · doi:10.1002/mba2.70032
openalex publication_date 2025/11/22 · openalex created_date 2025/11/23 · openalex updated_date 2026/07/23
The dual-targeting NICER (nanovesicle system integrating CSC-specific antigen display, epigenetic nano-regulator encapsulation, and dendritic-cell-targeting aptamer) nanovaccine created by Yanlian Yang's team eradicates both cancer stem cells (CSCs) and bulk tumors to prevent postoperative recurrence [1], addressing a major clinical challenge in solid tumor therapy where conventional treatments fail to eliminate therapy-resistant CSCs [2, 3]. This breakthrough strategy overcomes limitations of dendritic cell vaccines (hampered by CSC antigen scarcity [4] and conventional tumor vaccines (neglecting CSC targeting [5]. NICER, which stands for Integrated Nanovaccine for Cancer Eradication and Recurrence Prevention, consists of three complementary components (Figure 1) [1]. The core carrier consists of antigenically enriched nanovesicles (ANVs) sourced from tumor cells overexpressing ALDH1A1, a universal CSC marker, facilitating the simultaneous display of a CSC-specific antigen (ALDH1A1) and tumor-associated antigens (TAAs) for the concurrent targeting of CSCs and bulk tumor cells. In these ANVs, the team encapsulated an epigenetic nanoregulator (ENR) that delivers small interfering RNA (siRNA) targeting the YTHDF1 protein; by inhibiting YTHDF1-mediated translation of essential lysosomal protease genes in DCs, the ENR reduces antigen degradation within lysosomes and promotes antigen release into the cytosol, thereby enhancing antigen cross-presentation efficiency through the MHC I pathway. Moreover, the surface attachment of a DC-SIGN-specific aptamer leads the NICER vaccine to dendritic cells located in lymph nodes, significantly increasing its accumulation in these essential immunological induction locations. Experimental validation confirmed that NICER epigenetically reprogramed DC activity, inducing robust antitumor effects across several models. To be more specific, in murine breast cancer (4T1) and melanoma (B16) models, NICER effectively activated antigen-specific CD8⁺ T cells, as demonstrated by significantly increased IFNγ secretion (***p < 0.0001 compared to the control vaccine). Concurrently, it enabled the promotion of a substantial pool of splenic CD44⁺ memory T cells, as indicated by a significant increase in the frequency of gp70/ALDH1A1 tetramer-positive cells. Furthermore, by employing a tumor model that was enriched with CSCs, NICER was able to significantly decrease the frequency of postoperative residual ALDH1A1⁺ CSCs by roughly 76% (from 3.29% to 0.79%, *p < 0.0001 in comparison to the control), therefore effectively inhibiting the regrowth of CSC-driven tumors. In the context of surgical lung metastasis, NICER treatment succeeded in achieving a decrease of metastatic nodules by 75% (p = 0.0013 compared to the control), and it also increased the median survival by roughly twofold. Interestingly, concomitant delivery of a low-dose anti-PD-1 antibody produced synergistic benefits, improving survival rates even further. The fundamental novelty of NICER lies in the synergistic combination of epigenetically enhanced cross-presentation and dual-antigen targeting. Importantly, the viability of creating customized NICER vaccines from patient tumor tissues has been clearly shown, as evidenced by a 70% decrease in tumor burden in the mouse mammary tumor virus-polyomavirus middle T antigen spontaneous metastasis model (***p < 0.0001 compared to control), as well as a great safety record free of elevated organ toxicity. To advance this strategy clinically, future research could prioritize three areas of optimization: specifically, the incorporation of ligands for DNGR-1, which is a receptor that is highly expressed on the cross-presenting cDC1 subset, to enhance the efficiency of antigen cross-presentation; the rigorous assessment of potential off-target effects on tumor microenvironmental cells (taking into consideration the low-level expression of ALDH1A1 in some tumor-associated fibroblasts) to modify targeting specificity; and the development of automated nanovesicle production processes to enable scalable manufacturing for widespread clinical deployment. When considered as a whole, the NICER platform presents a unique approach to the fight against postoperative cancer recurrence. The platform's shown synergy with immune checkpoint inhibitors highlights the significant potential for future clinical combination regimens. Ting Wang: writing – original draft, writing – review and editing. Zhiqing Pang: writing – original draft, writing – review and editing. All authors have read and approved the final manuscript. The authors have nothing to report. This review article did not involve new animal or human studies. The authors declare no conflicts of interest. The data supporting this review are available within the article and its cited references. Further datasets can be obtained from the corresponding author upon reasonable request.