Photo-immuno nano-bomb for co-delivery of Ce6 and R837 potentiates immunogenic cell death and amplifies anti-tumor efficacy in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) remains a formidable clinical challenge, constrained by the drawbacks of current treatments such as functional loss from surgery, radioresistance, and low adherence to protracted topical regimens. To address these issues, we designed a "photo-immuno nano-bomb" composed of polydopamine nanoparticles (PDA NPs) for co-delivering the photosensitizer chlorin e6 (Ce6) and toll-like receptor 7 agonist imiquimod (R837), thereby integrating photothermal (PTT), photodynamic (PDT), and immunotherapeutic modalities. The system utilizes π-π stacking to achieve high drug loading and stability while exhibiting a dual stimuli-responsive release profile - governed by pH-dependent surface charge alteration and photothermally triggered payload liberation - enabling more precise spatiotemporal control over combination therapy. Remarkably, the nanoformulation potently suppressed tumor cell proliferation, migration, and invasion <i>in vitro</i> by activating apoptotic pathways. Mechanistic studies revealed that under dual-wavelength laser irradiation (660 + 808 nm), PDA-mediated PTT enhanced cellular internalization of the nanoplatform and further augmented singlet oxygen generation, ultimately inducing mitochondrial dysfunction and cytoskeletal disintegration. This synergistic action provoked severe cellular oxidative stress and organelle damage, culminating in robust immunogenic cell death (ICD). Additionally, the platform demonstrated excellent biocompatibility, achieving complete tumor regression <i>in vivo</i>, outperforming all mono- and combination therapy controls. Thus, this "photo-immuno nano-bomb" multimodal strategy represents a promising therapeutic alternative for advanced cSCC, delivering superior efficacy through coordinated molecular mechanisms and minimized systemic toxicity.