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

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-NaYF₄: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 (≈10² 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.