Tumor microenvironment-responsive NanoShield for precision photodynamic and photothermal synergistic cancer therapy with mitigated skin phototoxicity.

Abstract

Photodynamic therapy (PDT) is a highly promising non-invasive cancer treatment but is often hampered by severe skin phototoxicity arising from the nonspecific distribution of photosensitizers (PSs). Stimuli-responsive aggregation-induced emission (AIE) PSs show great promise for enhancing selectivity and efficacy. However, challenges such as complex synthesis and inadequate in vivo phototoxicity evaluations still need to be addressed. Furthermore, single-modality PDT frequently yields suboptimal therapeutic outcomes. To address these limitations, we present a tumor microenvironment (TME)-responsive AIE NanoShield (P-AD@PD), a precision theranostic nanoplatform engineered for synergistic phototherapy with mitigated skin phototoxicity. The NanoShield comprises a poly(N-isopropylacrylamide-co-acrylic acid) (PNA) nanogel system encapsulating an AIE PS (AD), shielded by a polydopamine (PDA) coating to enhance photoprotection. During systemic circulation, the PDA layer quenches AD photoactivity, minimizing skin phototoxicity. Upon tumor accumulation, it triggers hyperthermia for photothermal therapy (PTT) and gradually degrades within the TME to reactivate AD for precise PDT. This sequential PTT-PDT regimen amplifies therapeutic efficacy through dual-mode imaging while mitigating off-target toxicity. The PDA-based shielding strategy offers broad applicability across PSs, providing a universal approach to enhance PDT efficacy and safety.