NCL (Nucleolin)

We demonstrate that this system specifically degrades nucleolin and PD-L1 on tumor cells under acidic conditions, exerting direct cytotoxicity on tumor cells and alleviating immunosuppression in immune cells. As a proof of concept, DOPD-mediated tumor immunotherapy was validated in a xenograft mouse model, underscoring its potential as a programmable platform for precise protein degradation.

Through analysis of representative clinical programs, including the systemic nucleolin-targeting aptamer AS1411, the microenvironment-modulating CXCL12 inhibitor NOX-A12, and the locally administered personalized platform AM003, this review highlights how delivery strategy, target context, and clinical deployment critically shape therapeutic outcomes. Recurrent translational barriers related to systemic exposure, tumor accessibility, regulatory pathways, and competition with established modalities are identified, together with lessons from both failed and emerging programs. Finally, we discuss practical strategies to improve clinical alignment, including human-relevant selection models, localized or combination therapies, and AI-assisted design, positioning aptamers for context-appropriate roles in future precision oncology.

These PROTACs induced NCL- and MDM2-dependent ubiquitination and degradation of VEGFR2 or EGFR in GBM cells, demonstrating potent anti-tumour activity. Collectively, our findings identify EV-transferred NCL as a key mediator of BTB formation and a functional transcytosis receptor for AS1411, providing a promising strategy for developing BTB-permeable, targeted therapy for GBM.

Although most aptamer-based checkpoint inhibitors remain in preclinical stages, early phase clinical investigations (primarily with C-X-C motif chemokine ligand 12 (CXCL12)-targeting Spiegelmer NOX-A12 in combination settings, as well as earlier programs such as AS1411 targeting nucleolin) have demonstrated effective inhibition of immune checkpoint signaling, reactivation of T-cell function, and synergistic effects when combined with existing immunotherapies. Preclinical and early phase clinical investigations have demonstrated that aptamers can effectively inhibit immune checkpoint signaling, reactivate T-cell function, and potentiate synergistic effects when combined with existing immunotherapies. By critically evaluating current progress and identifying key translational challenges, this review provides strategic insights into the future development of aptamer-based immunotherapeutic platforms, ultimately guiding the advancement of more precise, cost-effective, and personalized cancer treatment modalities.

Herein, a cross-shaped DNA skeleton was rationally engineered by leveraging programmable DNA assembly and AS1411 aptamer-mediated tumor targeting to achieve specific activation of the cGAS-STING pathway...In vitro and in vivo evaluations further validated that the DNA scaffold not only triggered innate immune activation but also inhibited tumor progression in TNBC models. Overall, this work provides a promising strategy for the development of safe and effective TNBC immunotherapy.

Importantly, modulation of ATP6AP1 expression showed minimal effects on normal breast epithelial cells. Collectively, these findings identify ATP6AP1 as a key downstream mediator of AS1411 and support its potential as a therapeutic target in TNBC.

To address this, we developed a polymer-lipid hybrid nanoparticle functionalized with the AS1411 aptamer, targeting nucleolin to facilitate nucleus-directed delivery...Further evaluation targeting the Lcn2 gene demonstrated higher knockout efficacy and a more potent inhibition of breast cancer cell proliferation. These findings indicate that aptamer-mediated nuclear targeting enhances CRISPR/Cas9 editing efficacy and may offer the potential to advance the performance of non-viral gene therapies.

Additionally, the versatility and adaptability of the platform have been confirmed on the PTK7 protein and the FGFR2 protein. The ApMPL platform will be valuable for discovering membrane protein interactions, elucidating critical signaling networks, and facilitating therapeutic target identification.

First-line therapies, such as gemcitabine and nab-paclitaxel, often lead to unexpected side effects. Our findings also confirmed that SMCC- and SPDMV-linked ApDCs retained stability in human serum for up to 48 h. Flow cytometry and confocal microscopy analyses further illustrated the excellent targeting capabilities of these conjugates in pancreatic cancer cell lines PANC-1 and MIA PaCa-2, in contrast to normal cells such as MIHA (normal human liver cells). Two candidates, 5'-NucA-SMCC-DM1 and 5'-NucA-SPDMV-DM1, were selected based on in vitro evaluations and exhibited potent antitumor efficacy with significantly decreased toxicity to the liver and heart compared with DM1 alone in xenografted mice.

The AS1411 aptamer was embedded at the end of the DNA linker to effectively target nucleolins that are overexpressed in tumor cells...Ultimately, the quantitative relation between MRI signals and local miR-21 concentration was established in vivo. These results indicated the potential of nanoprobes for tumor-related genes diagnosis and quantification, further affirming the possibility of prompt and precise tumor diagnosis.

Conventional antibody-based modalities, including antibody-drug conjugates (e.g., sacituzumab govitecan against TROP2) and checkpoint inhibitors (e.g., atezolizumab for programmed death-ligand 1 [PD-L1]), leverage antibody-dependent cellular cytotoxicity, direct antigen blockade, and immune activation to combat tumor growth and evasion...Peptides, such as cell-penetrating variants and vaccines (e.g., HER2-derived AE37), disrupt oncogenic pathways, enable precise drug delivery via conjugates, and elicit antigen-specific immune responses. Aptamers provide high-affinity binding to antigens like nucleolin (e.g., AS1411), supporting targeted delivery and tumor microenvironment modulation. Together, these platforms hold strong potential to overcome chemoresistance, enable subtype-specific treatment personalization, and improve outcomes through synergistic combinations, advancing precision oncology in TNBC.