Rational design of multicavity interconnected yolk-shell nanocomposite for enhanced dual-PTT and CDT in potent antitumor photothermal immunotherapy

• The unique dual-PTT multicavity interconnected yolk-shell nanostructure enhances light absorption through internal reflections, achieving superior photothermal conversion while enabling precise control over ICD-inducer Cel delivery. • Near-infrared-triggered Cel release simultaneously suppresses HSP90 to sensitize tumors to PTT and elevates H 2 O 2 levels, driving a self-amplifying therapeutic cascade through Fenton/catalase-like reactions that intensify chemodynamic therapy and oxygen generation. • Cel-mediated and its synergistically enhanced PTT, CDT, and O2 production collectively induce robust ICD, substantially amplifying antitumor immunogenicity. Complete regression of residual tumors following photothermal therapy (PTT) critically depends on immune activation. However, PTT-induced immune stimulation alone often fails to fully activate robust anti-tumor responses. Photothermal immunotherapy, which integrates phototherapy with immunotherapy, has gained prominence for enhancing immune efficacy via the induction of immunogenic cell death (ICD). We engineered a multicavity interconnected yolk-shell nanocomposite using wet-chemical etching and sonication-assisted method. The nanocomposite consists of eight-corner-etched Prussian Blue (PB) core encased within a polydopamine (PDA) shell, which is then loaded with celastrol (Cel) and further wrapped with hyaluronic acid (HA), forming a PB@PDA/Cel@HA nanocomposite (denoted as YS-PPCH). The unique dual-PTT nanostructure of YS-PPCH enhances light absorption through internal reflections, enabling efficient photothermal conversion while serving as a stable platform for the controlled encapsulation and release of Cel, an ICD inducer. Under NIR irradiation, Cel release inhibits HSP90 expression, sensitizing tumors to PTT. Concurrently, Cel elevates endogenous hydrogen peroxide (H 2 O 2 ) levels, thereby enhancing chemodynamic therapy (CDT) and O 2 production through Fenton and catalase-like reactions between Fe 2+ /Fe 3+ within PB and H 2 O 2 . Cel-mediated and its synergistically enhanced PTT, CDT, and O 2 production collectively induce robust ICD. This rationally designed nanocomposite presents a promising strategy for amplifying antitumor immunogenicity.