Facile tailoring of photosensitizers (PSs) with advanced and synergetic properties is highly expected to broaden and deepen the photodynamic therapy (PDT) applications. Herein, a catalyst-free thiol-yne click reaction was employed to develop the sulfur atom-based PSs by using the in situ formed sulfur "heavy atom effect" to enhance the intersystem crossing (ISC), while such effect can be remarkably magnified by the polymerization. The introduction of tetraphenylpyrazine-based aggregation-induced emission (AIE) unit was also advantageous in PS design by suppressing their non-radiative decay to facilitate the ISC in the aggregated state. Besides, the resulting sulfur atom electron donor, together with double bond π bridge and AIE electron acceptor, created a D-π-A molecular system with good two-photon excitation properties. Combined with the high singlet oxygen generation efficiency, the fabricated polymer nanoparticles exhibited an excellent in vitro two photon-excited PDT towards the cancer cells, therefore possessing a huge potential for the deep-tissue disease therapy.