AbstractWe describe porous silicon nanoparticles (pSiNP) chemically functionalized with an analog of mannose 6‐phosphate (AMFA) and a porphyrin derivative to target aggressive pediatric Rhabdomyosarcoma (RMS) tumor cells. Our findings demonstrate that the pSiNP@AMFA@porphyrin nanosystems are efficiently internalized by RMS cells, which overexpress mannose 6‐phosphate receptors, and induce cytotoxicity and phototoxicity when exposed to two‐photon excitation light. These results provide an interesting potential for targeting and treating RMS pediatric tumors.