“Mix‐and‐Match”: Self‐Sorting Assembly Governed Supramolecular Polymeric Nanomedicine for Boosting Combined Chemo/Phototherapy

Abstract Precise cancer nanomedicine requires rational molecular instructions of therapeutic agents. Harnessing the structure‐property‐function relationships represents a practical strategy toward smart and effective nanomedicine. A structurally novel hydrogen‐bonded (H‐bonded) supramolecular nanoformulation generated by orthogonal self‐sorting assembly of chemo‐prodrug (FPtF) and phototherapeutics (BPeB) is here reported, to reach an autonomous nanomedicine with improved anti‐tumor efficacy by combining chemo/phototherapy (CT/PT). The high‐fidelity of H‐bonding modularity from privileged heterocomplementary diaminopyridine/5‐fluorouracil (DAP/FU) and Hamilton wedge/barbiturate (HW/Ba) pairs, respectively enable the precise spatial control of binding interactions toward FPtF and BPeB, in turn allowing the self‐sorting process and specific “mix‐and‐match” capability. To directly stimulate phototherapy from BPeB via near‐infrared (NIR) light, spectral matched upconversion nanoparticles (UCNPs, β‐NaYF 4 :Yb,Er) are encapsulated simultaneously. As a result, supramolecular polymeric nanomicelles, i.e., F/B/U@PHDO, are readily fabricated. Moreover, distinct H‐bonding association constant (Ka) of DAP/FU (≈10 2 M −1 ) and HW/Ba (≈10 4‐5 M −1 ) pairs reflect different strengths and stabilities of H‐bonds, thus endowing the programmable H‐bonding dissociation, accompanied with the chemo‐prodrug release through pH/thermal‐stimuli. Therapeutic regime with appreciated anti‐tumor outcomes is ultimately accomplished via combined CT/PT. The privileged opportunities offered by self‐sorting design are anticipated to point to new paradigm toward precise nanomedicine for cancer therapy.