Alkyl Chain Regulation‐Based Biomimetic Nanoparticles: Excellent Stability and Photothermal Efficiency for Personalized Tumor Targeted Therapy

ABSTRACT The relationship between the structure of the alkyl chain of organic photothermal agents (PTAs), their ability to form stable nanoparticles, and the resulting efficacy of photothermal therapy (PTT) is unclear, substantially hindering the application of biomimetic PTA‐based nanoparticles in PTT. In this study, we designed three Y6‐based photothermal molecules with distinct alkyl chain architectures: Y6‐0 (no alkyl chain), Y6‐nC11 (linear), and Y6‐iC11 (branched). Biomimetic nanoparticles incorporating these molecules were constructed (DP@Y6‐0, DP@Y6‐nC11, and DP@Y6‐iC11). The structure–property relationships between the alkyl chain structure, photothermal performance, and storage stability were investigated. Molecules with alkyl chain modifications (Y6‐nC11 and Y6‐iC11) were found to enhance liposome‐binding affinity via hydrophobic interactions. Long alkyl chains promoted more ordered molecular packing, branched side chains (compared to their linear counterparts), and disrupted π–π stacking distances, thereby diminishing photothermal performance. Therefore, the DP@Y6‐nC11 nanoparticles exhibited a more pronounced redshift in absorption and superior photothermal performance compared to DP@Y6‐iC11. Furthermore, fusion with tumor cell membranes significantly enhanced the tumor‐specific accumulation of these nanoparticles. Overall, M@DP@Y6‐nC11 nanoparticles exhibited excellent photothermal therapeutic efficacy in personalized tumor‐specific models.