Abstract

Despite remarkable advancements in nanocarrier-based combination therapy strategies, the therapeutic efficacy and patient well-being are still substantially affected by tumor heterogeneity and the complexities of drug carrier engineering. Here, a new surface charge-actuated mesoporous silica-based multifunctional nanoplatform, MSN-DOX@PDA-LM, was exploited to integrate chemotherapy, photothermal therapy (PTT), stimuli-responsive drug release, and targeted tumor delivery. The platform comprises a doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) core coated with polydopamine (PDA), and is further encapsulated within a polymer shell consisting of a pH-responsive, charge-reversible zwitterionic polymer P(2-aminoethyl methacrylate hydrochloride - co - (2-((2-(methacryloyloxy)ethyl)dimethylammonio)acetyl)(phenylsulfonyl)amide) (PAM) and a glycopolymer P(2-aminoethyl methacrylate hydrochloride - co - 2-lactobionamidoethyl methacrylamide) (PAL) that exhibits high affinity for tumor cells. During in vivo delivery, the PDA coating serves as a gatekeeper against DOX leakage. PAM not only effectively prolongs in vivo circulation and enhances tumor accumulation but also undergoes charge reversal upon reaching the acidic tumor microenvironment (TME), which - together with the high affinity of PAL for tumor cells - jointly facilitates precise tumor targeting and promotes cellular uptake and penetration. Intracellularly, PDA provides photothermal activity via strong near-infrared (NIR) absorption to induce thermal ablation for improved chemosensitivity, while simultaneously releasing DOX in response to acidic conditions, thereby realizing chemo-photothermal combination therapy. In vitro and in vivo experiments demonstrated the expected enhanced anti-tumor efficacy. Overall, this surface-engineered MSN-DOX@PDA-LM provides a facile yet promising approach for the effective combination cancer therapy.