Dual-Targeting Multivalent Aptamer-Drug Hybrids for Synergistic Cancer Immunotherapy.

Area of Science:

• Biotechnology and Nanomedicine
• Cancer Therapeutics
• Immunology

Background:

• Existing targeted drug conjugates (TDCs) often use single-antigen targeting and single payloads, limiting efficacy in heterogeneous tumors.
• There is a need for advanced TDCs that can deliver multiple therapeutic agents and engage orthogonal mechanisms of action.

Purpose of the Study:

• To develop and evaluate circular, dual-targeting multivalent aptamer-drug hybrids (^Dualo-mvApDHs^D/S) for synergistic chemo-immunotherapy.
• To investigate the codelivery of doxorubicin (Dox) and a STING agonist (diABZI) for enhanced tumor-specific uptake and immune response activation.

Main Methods:

• Designed programmable DNA scaffolds with defined valency and high loading capacity for aptamer-drug conjugation.
• Engineered ^Dualo-mvApDHs^D/S to simultaneously target c-Met and CD71 receptors.
• Evaluated in vitro and in vivo efficacy, including tumor accumulation, immunogenic cell death induction, STING pathway activation, and immune cell modulation using single-cell RNA and TCR sequencing.

Main Results:

• ^Dualo-mvApDHs^D/S achieved enhanced tumor-specific uptake via heteromultireceptor-mediated endocytosis and efficient intracellular delivery.
• Codelivering Dox and diABZI induced immunogenic cell death and activated type I interferon responses, remodeling the immunosuppressive tumor microenvironment.
• Combination therapy promoted dendritic cell and CD8+ T cell responses, and synergized with PD-1 blockade for durable tumor eradication and long-term protection.

Conclusions:

• Multivalent aptamer-drug hybrids represent a versatile platform for multitarget, multipayload precision therapeutics.
• This dual-targeting, dual-payload strategy holds significant potential for next-generation targeted drug conjugate design in cancer therapy.