Conferring catalytic defects in sonosensitizers is of paramount importance in reinforcing sonodynamic therapy. However, the formation of such 0D defects is governed by the Schottky defect principle. Herein, 2D catalytic planar defects are designed within Ti3C2 sheets to address this challenge. These specific planar slip dislocations with abundant Ti3+ species (Ti3C2‐SD(Ti3+)) can yield surface‐bound O due to the effective activation of O2, thus resulting in a substantial amount of 1O2 generation and the 99.72% ± 0.03% bactericidal capability subject to ultrasound (US) stimulation. It is discovered that the 2D catalytic planar defects can intervene in electron transfer through the phonon drag effect—a coupling effect between surface electrons and US‐triggered phonons—that simultaneously contributes to a dramatic decrease in O2 activation energy from 1.65 to 0.06 eV. This design has achieved a qualitative leap in which the US catalytic site has transformed from 0D to 2D. Moreover, it is revealed that the electron origin, electron transfer, and visible O2 activation pathway triggered by US can be attributed to the phonon–electron coupling effect. After coating with neutrophil membrane (NM) proteins, the NM‐Ti3C2‐SD(Ti3+) sheets further demonstrate a 6‐log10 reduction in methicillin‐resistant Staphylococcus aureus burden in the infected bony tissue.

Multidrug‐resistant (MDR) bacteria are emerging and disseminating rapidly, undoubtedly posing an urgent threat to global public health. One particular concern is that MDR Gram‐negative bacteria are immunized to available antibiotics owing to a series of biogenetic effects, including the β‐barrel assembly machine (BAM complex) in the outer membrane, MDR efflux pumps, and enzymatic degradation/modification, which are known to induce antibiotic resistance (AbR). Here, this work identifies that the AbR mechanisms of MDR Escherichia coli become compromised and sensitive again to conventional antibiotics, when the temperature of infected tissues is elevated to ≈50 °C in situ. This thought is realized by the microwave‐driven poly(lactic‐co‐glycolic acid) microparticles that may effectively convert electromagnetic radiation to thermal energy. The microwave hyperthermia (MWH) therapy not only interrupts the essential surface‐exposed BamA protein of the BAM complex, but also enhances the permeability of the outer membrane and inhibits the action of MDR efflux pumps. MWH also impairs the hydrogen bond interaction between the catalytic residues of bacterial enzymes and functional groups of antibiotic molecules. Lastly, this work demonstrates these combined inhibitors can revitalize the bactericidal effects of conventional antibiotics in MDR Escherichia coli‐associated deep tissue infections.