Friends Fight the Foes: Synergistic Low‐Temperature Photothermal/Chemo/Gas Therapy for Conquering Cancer Cells

Abstract Photothermal therapy (PTT) integrated with nanotechnology reflects an essential modality towards cancer treatment, however, this strategy often encounters considerable issues such as low therapeutic efficiency and excessive heat that need to be addressed. In this context, a structurally novel intelligent polymeric antitumor nanobomb (GEM806@PETU(CO)) is highlighted, featuring hydrogen‐bonds (H‐bonds) linked gemcitabine (GEM)‐IR780 conjugate (GEM806), along with metal‐chelation locked carbon monoxide (CO) reservoir, towards synergistic low‐temperature photothermal/chemo/gas therapy (LTPTT/CT/GT). To do so, an amphiphilic diblock copolymer vehicle PETU(CO) is firstly constructed, bearing hydrophilic and biocompatible polyethylene glycol (PEG) block, importantly, rationally designed hydrophobic block reflects triple functionalities, i.e., pH responsive charge‐reversal, stable CO‐storage scaffold, and H‐bonding ureidoimidazole (UIM) motifs towards GEM. Meanwhile, chemotherapeutic GEM is tethered onto photothermal agent IR780, endowing multifunctional prodrug GEM806 that combines H‐bonding site, chemotherapeutic drug, photothermal and NIR fluorescence imaging in single formulation. Thanks to H‐bonding UIM/GEM association mediated self‐assembly, GEM806 is uploaded and supramolecular intelligent nanobomb GEM806@PETU(CO) is thus created, featuring spatiotemporally controlled activation and synergistic therapeutics, including: 1) pH/thermal responsive GEM806‐release towards CT/PTT modalities, 2) H 2 O 2 /thermal responsive CO‐release for boosting LTPTT/GT, 3) CO‐enhanced chemotherapy sensitivity by ferroptosis pathway. Such modular allies of nanobomb render advanced paradigm towards precision cancer therapy and potential clinical impact.