LAUSR

Tumor microenvironment-responsive multi-modal synergistic theranostic strategies can significantly improve the therapeutic efficacy while avoiding severe side effects. Inspired by the fact that special morphology could enhance photothermal conversion efficiency (PCE) and cellular delivery, we developed an acidic tumor microenvironment-responsive shape-reversal metal-organic virus-inspired nanodrug for enhancing near-infrared (NIR)-II PCE, increasing cell adhesion, and activating tumor targeting. Firstly, NIR-I fluorescence probe (IR825), chemo-drug (pemetrexed, PEM), rare-earth metal ion (Nd(III)), were chosen to synthesize virus-like nanodrug via coordination-driven assembly. Then, the spike-like surface of nanodrug was further camouflaged by acidity-sensitive PEG "shell" to create virus-cored and sphere-shelled hierarchical nano-assemblies, which could efficiently prevent immune clearance and prolong systemic circulation. Interestingly, the acidic tumor microenvironment could trigger the shell detachment of nano-assemblies for shape reversal to produce virus-like surface followed by re-exposure of PEM, to synergistically amplify the cellular internalization while enhancing NIR-II PCE. By utilizing the shell-detached virus-like nanodrug core, the tumor microenvironment-specific enhanced NIR-II photothermal-chemotherapy can be realized under the precise guidance of fluorescence/photoacoustic imaging, thereby achieving complete tumor elimination without recurrence in a single treatment cycle. We envision that integrating tumor microenvironment-responsive ability with "sphere-to-virus" shape reversal will provide a promising strategy for biomimetic targeted cancer therapy.