| Summary: | Bacteria‐mediated drug delivery systems comprising nanotherapeutics conjugated onto bacteria synergistically augment the efficacy of both therapeutic modalities in cancer therapy. Nanocarriers preserve therapeutics’ bioavailability and reduce systemic toxicity, while bacteria selectively colonize the cancerous tissue, impart intrinsic and immune‐mediated antitumor effects, and propel nanotherapeutics interstitially. The optimal bacteria–nanoparticle (NP) conjugates will carry the maximal NP load with minimal motility speed hindrance for effective interstitial distribution. Furthermore, a well‐defined and repeatable NP attachment density distribution is crucial to determining these biohybrid systems’ efficacious dosage and robust performance. Herein, our nanoscale bacteria‐enabled autonomous delivery system (NanoBEADS) platform is utilized to investigate the effects of assembly process parameters of mixing method, volume, and duration on NP attachment density and repeatability. The effect of linkage chemistry and NP size on NP attachment density, viability, growth rate, and motility of NanoBEADS is also evaluated. It is shown that the linkage chemistry impacts NP attachment density while the self‐assembly process parameters affect the repeatability and, to a lesser extent, attachment density. Lastly, the attachment density affects NanoBEADS’ growth rate and motility in an NP size‐dependent manner. These findings will contribute to the development of scalable and repeatable bacteria–NP biohybrids for applications in drug delivery and beyond. An interactive preprint version of the article can be found here: https://www.authorea.com/doi/full/10.22541/au.163100509.93917936.
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