Targeted drug delivery using antibody–drug conjugates has attracted great attention due to its enhanced therapeutic efficacy compared to traditional chemotherapy. However, the development has been limited due to a low drug-to-antibody ratio and laborious linker-payload optimization. Herein, we present a simple and efficient strategy to combine the favorable features of polymeric nanocarriers with antibodies to generate an antibody–nanogel conjugate (ANC) platform for targeted delivery of cytotoxic agents. Our nanogels stably encapsulate several chemotherapeutic agents with a wide range of mechanisms of action and solubility. We showcase the targetability of ANCs and their selective killing of cancer cells over-expressing disease-relevant antigens such as human epidermal growth factor receptor 2, epidermal growth factor receptor, and tumor-specific mucin 1, which cover a broad range of breast cancer cell types while maintaining low to no toxicity to non-targeted cells. Overall, our system represents a versatile approach that could impact next-generation nanomedicine in antibody-targeted therapeutics.

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Targeted delivery of therapeutics using antibody–nanogel conjugates (ANCs) with a high drug-to-antibody ratio has the potential to overcome some of the inherent limitations of antibody–drug conjugates (ADCs). ANC platforms with simple preparation methods and precise tunability to evaluate structure–activity relationships will greatly contribute to translating this promise into clinical reality. In this work, using trastuzumab as a model antibody, we demonstrate a block copolymer-based ANC platform that allows highly efficient antibody conjugation and formulation. In addition to showcasing the advantages of using an inverse electron-demand Diels–Alder (iEDDA)-based antibody conjugation, we evaluate the influence of antibody surface density and conjugation site on the nanogels upon the targeting capability of ANCs. We show that compared to traditional strain-promoted alkyne–azide cycloadditions, the preparation of ANCs using iEDDA provides significantly higher efficiency, which results in a shortened reaction time, simplified purification process, and enhanced targeting toward cancer cells. We also find that a site-specific disulfide-rebridging method in antibodies offers similar targeting abilities as the more indiscriminate lysine-based conjugation method. The more efficient bioconjugation using iEDDA allows us to optimize the avidity by fine-tuning the surface density of antibodies on the nanogel. Finally, with trastuzumab-mertansine (DM1) antibody–drug combination, our ANC demonstrates superior activities in vitro compared to the corresponding ADC, further highlighting the potential of ANCs in future clinical translation.