Gas　therapy　has　emerged　as　a　forceful　strategy　for　augmenting　the　effects　of　chemotherapeutic　drugs　against　cancer　cells.　However,　it　remains　extremely　challenging　to　effectively　deliver　gas　into　tissues　of　interest　and　unravel　its　underlying　mechanisms.　Herein,　we　designed　a　near-infrared　(NIR)　light-switchable　nitric　oxide　(NO)　delivery　nanosystem　for　high-efficacy　multidrug　resistance　(MDR)　reversal　in　cancer　therapy　based　on　a　yolk-shell　upconverting　nanoparticles@magnesium　silica　(UCNP@MgSiO3).　The　internal　hollow　cavity　and　flower-like　mesoporous　shell　of　UCNPs@MgSiO3　not　only　enabled　a　significantly　high　encapsulation　capacity　for　the　NO　precursor　(BNN6)　and　doxorubicin　(DOX)　but　also　allowed　the　enhanced　cellular　uptake,　resulting　in　NIR-triggered　NO　generation　and　low　pH-triggered　DOX　release　in　cancer　cells.　Mechanistically,　intracellular　NO　can　downregulate　the　drug　efflux-related　P-glycoprotein　and　adenosine　5′-triphosphate-binding　cassette　transporters,　thereby　increasing　the　DOX　accumulation　in　the　cell　nuclei.　Such　combination　therapy　of　NO　and　DOX　induced　the　apoptosis　of　MDR　cells　and　completely　inhibited　in　vivo　MDR　tumor　growth.　We　further　elucidated　the　therapy　mechanism　via　proteomic　profiling,　showcasing　the　downregulation　of　the　ubiquitin-proteasome　pathway　and　nuclear　factor　kappa-B　signaling　pathway　in　the　NO-treated　MDR　cells.　Therefore,　our　findings　develop　a　promising　nanoscale　gas/drug　delivery　paradigm　for　fighting　MDR　tumors　and　providing　molecular　insights　into　cancer　therapy.　Copyright　©　2020　American　Chemical　Society.