The photoluminescence properties of single-walled carbon nanotubes (SWCNTs), which originate from quantum confined surface excitons, have been exploited for a variety of biological applications, including fluorescence imaging 1 , single-particle tracking , and biosensing . These applications take advantage of the nanotube's unique photophysical traits, such as photoluminescence in the near-infrared and shortwave infrared regions of the spectrum, as well as their non-blinking and photostable emission. In biosensing, the excitonic fluorescence of SWCNTs and their distinctive single-atom-thick geometry are exploited to translate molecular recognition events into detectable signals. The optoelectronic properties of SWCNT, and similar shell-like nanomaterials, are highly sensitive to physicochemical perturbations that occur on or near the surface, enabling detection of local changes with single-molecule sensitivity. This has been successfully demonstrated in functionalized SWCNTs. Biosensing applications of SWCNTs require functionalization with moieties that tailor the pristine surface of the nanomaterials, creating configurations ideal for analyte binding. Among the various strategies for developing SWCNT-based biosensors, noncovalent functionalization with amphiphilic biopolymers, particularly oligonucleotides (e.g., single-strand DNA, ssDNA) remains a predominant strategy. This approach enables versatile patterning of the nanotube surface with chemically rich and structurally diverse oligonucleotide motifs. This strategy has enabled successful applications of ssDNA-SWCNT hybrids in diverse fields, including nanotube-based device manufacturing , chirality sorting , and SWCNT lattice remodeling . The conjugation of ssDNA to the surface of nanotubes through noncovalent selfassembly sculpts specific analyte binding pockets that are absent on non-functionalized surfaces, enabling their use in biosensing applications. Despite several successful applications, a coherent strategy for developing biosensors from ssDNA-SWCNT bio-nanohybrids remains elusive. This challenge stems in part from a lack of understanding of how analyte binding in ssDNA-nanotube bio-nano conjugates modulates the optical properties of the nanotubes. The chemical diversity of nanotube surface topologies that can be engineered with ssDNA sequences is vast and depends on oligonucleotide length and sequence chemistry. Matching this broad chemical space to potential analytes through screening approaches is an arduous task, and success with this approach has been limited. Recent studies have demonstrated that machine learning approaches hold promise for predicting new ssDNA sequences in ssDNA-SWCNTs for sensing small molecular analytes. An alternative approach is rational design, where mechanistic understanding of how ssDNA-SWCNT biosensors function guides sensor development. Such understanding could streamline the development of biosensors by informing the selection or chemical modification of ssDNA sequences and the design of nanotube functionalization strategies, ultimately leading to more effective and predictable sensor development and performance.